EP0129051A2 - Substituted indoles - Google Patents

Abstract

2- (pyridyl and imidazolyl) indoles of the formula I <IMAGE> in which R1 is hydrogen or lower alkyl, Ar is in each case unsubstituted or substituted by lower alkyl, carboxy, lower alkoxycarbonyl or carbamoyl, 3-pyridyl or 1-imidazolyl, R2 and R3 independently are hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy, lower alkoxy, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy, lower alkoxycarbonyl or lower alkyl- (thio, sulfinyl or sulfonyl), or R2 and R3 together, on adjacent carbon atoms, are lower alkylene dioxy; A alkylene having 3 to 12 carbon atoms, the number of carbon atoms between the indole nucleus and group B being 3 to 12, alkenylene or alkynylene each having 2 to 12 carbon atoms, lower alkylenephenylene-lower (alkylene or alkenylene), lower alkylene-phenylene, Lower alkylene (thio or oxy) lower alkylene, lower alkylene (thio or oxy) phenylene or lower alkylene phenylene (thio or oxy) lower alkylene and B is carboxy, esterified carboxy, carbamoyl, mono- or di-lower alkylcarbamoyl, hydroxymethyl, cyano, hydroxycarbamoyl , 5-tetrazolyl or formyl; their imidazolyl or pyridyl N-oxides and their salts inhibit thromboxane synthetase. They are manufactured in a manner known per se.

Description

The invention relates to new 2-heteroarylindoles and processes for their preparation.

worin R₁ Wasserstoff oder Niederalkyl bedeutet, Ar jeweils für unsubstituiertes oder durch Niederalkyl, Carboxy, Niederalkoxy- carbonyl oder Carbamoyl substituiertes 3-Pyridyl oder 1-Imidazolyl steht, R₂ und R₃ unabhängig voneinander Wasserstoff, Niederalkyl, Halogen, Trifluormethyl, Hydroxy, Niederalkoxy, Carboxyniederalkyl, Niederalkoxycarbonyl-niederalkyl, Carboxy, Niederalkoxycarbonyl oder Niederalkyl-(thio, sulfinyl oder sulfonyl) bedeuten, oder R₂ und R₃ zusammen, an benachbarten Kohlenstoffatomen, Nied eralkylendioxy sind;The invention relates in particular to 2- (pyridyl and imidazolyl) indoles of the formula I.

where R _{1 is} hydrogen or lower alkyl, Ar in each case represents 3-pyridyl or 1-imidazolyl which is unsubstituted or substituted by lower alkyl, carboxy, lower alkoxycarbonyl or carbamoyl, R ₂ and R ₃ independently of one another are hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy, Lower alkoxy, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy, lower alkoxycarbonyl or lower alkyl- (thio, sulfinyl or sulfonyl), or R ₂ and R ₃ together, on adjacent carbon atoms, are lower alkylene dioxy;

A alkylene having 3 to 12 carbon atoms, the number of carbon atoms between the indole nucleus and group B being 3 to 12, alkenylene or alkynylene each having 2 to 12 Carbon atoms, lower alkylenephenylene lower (alkylene or alkenylene), lower alkylene phenylene, lower alkylene (thio or oxy) lower alkylene, lower alkylene (thio or oxy) phenylene or lower alkylenephenylene (thio or oxy) lower alkylene and

B represents carboxy, esterified carboxy, carbamoyl, mono- or di-lower alkylcarbamoyl, hydroxymethyl, cyano, hydroxycarbamoyl, 5-tetrazolyl or formyl; their imidazolyl or pyridyl-N-oxides, and their salts, in particular their pharmaceutically usable salts, and processes for their preparation, pharmaceutical preparations containing these compounds and their use for the production of pharmaceutical preparations or as pharmacologically active compounds.

• Ein Alkylenreist bedeutet Alkylen mit 3 bis 12 Kohlenstoffatomen, das geradkettig oder verzweigt sein kann, und vorzugsweise für Propylen, Butylen, Pentylen, Hexylen oder Heptylen steht, wobei die genannten Reste unsubstituiert oder durch eine oder mehrere Niederalkylgruppen substituiert sind, mit der Massgabe, dass die Summe der Kohlenstoffatome nicht grösser als 12 ist.

The general terms used above and below have the following meanings in the context of the present invention:

• An alkylene trip means alkylene with 3 to 12 carbon atoms, which can be straight-chain or branched, and preferably stands for propylene, butylene, pentylene, hexylene or heptylene, the radicals mentioned being unsubstituted or substituted by one or more lower alkyl groups, with the proviso that the sum of the carbon atoms is not greater than 12.

The term alkenylene means an alkenylene radical having 2 to 12 carbon atoms, which can be straight-chain or branched, and preferably for propenylene, 1- or 2-butenylene, 1- or 2-pentenylene, 1-, 2- or 3-hexenylene or 1- , 2-, 3- or 4-heptenylene. The radicals mentioned are unsubstituted or substituted by one or more lower alkyl groups, with the proviso that the sum of the carbon atoms does not exceed 12.

The term alkynylene denotes an alkynylene radical with 2 to 12 carbon atoms, which can be straight-chain or branched, and preferably for propinylene, 1- or 2-butinylene, 1- or 2-pentinylene, 1-, 2- or 3-hexinylene or 1- , 2-, 3- or 4-heptinylene stands. These radicals are unsubstituted or substituted by one or more lower alkyl groups, the sum of the carbon atoms not exceeding 12.

The term phenylene means 1,2-, 1,3- and preferably 1,4-phenylene.

The term "lower" in the above or below organic groups, radicals or compounds includes in particular those with at most 7, preferably 4 and especially 1, 2 or 3 carbon atoms.

Lower alkylene-phenylene, lower alkylene-phenylene-lower (alkylene or alkenylene) or lower alkylene- (thio or oxy) -phenylene preferably contain 1 to 4 and in particular 1 or 2 carbon atoms in each alkylene radical, and preferably 2 to 4 carbon atoms in each alkenylene radical. The lower alkylene or lower alkenylene radicals can be straight-chain or branched.

A lower alkylene (thio or oxy) lower alkylene group can be straight-chain or branched and have a total of 2 to 12, preferably 2 to 8, carbon atoms.

Lower alkyl preferably contains 1 to 4 carbon atoms and is e.g. ethyl, propyl or butyl and especially methyl.

Lower alkylene preferably contains 1 to 4 carbon atoms and is, for example, methylene, ethylene, 1,2- or 1,3-propylene or 1,2-, 1,3- or 1,4-butylene.

Lower alkylenedioxy preferably means ethylenedioxy or methylenedioxy.

Lower alkoxy preferably contains 1 to 4 carbon atoms and is e.g. Aethoxy, propoxy or especially methoxy. A lower alkyl (thio, sulfinyl or sulfonyl) group is preferably methylthio, methylsulfinyl or methylsulfonyl.

Lower alkoxycarbonyl preferably contains 1 to 4 carbon atoms in the alkoxy part and means e.g. Methoxycarbonyl, propoxycarbonyl or isopropoxycarbonyl and especially ethoxycarbonyl. Mono- (lower alkyl) carbamoyl preferably has 1 to 4 carbon atoms in the alkyl part and is e.g. N-methylcarbamoyl, N-propylcarbamoyl or in particular N-ethylcarbamoyl. Di- (lower alkyl) carbamoyl preferably contains 1 to 4 carbon atoms in each lower alkyl group and is e.g. for N, N-dimethylcarbamoyl, N-methyl-N-ethylcarbamoyl and in particular for N, N-diethylcarbamoyl.

Halogen is preferably fluorine or chlorine, but can also be bromine or iodine.

Esterified carboxy is preferably understood to mean those esters which can be used pharmaceutically, in particular those which can be converted into the corresponding free acids by solvolysis or under physiological conditions, for example lower alkoxycarbonyl, (amino, mono- or di-lower alkylamino) - substituted lower alkoxycarbonyl, carboxy-substituted lower alkoxycarbonyl, for example a-carboxy-substituted lower alkoxycarbonyl, lower alkoxycarbonyl-substituted lower alkoxycarbonyl, for example a-lower alkoxycarbonyl-substituted lower alkoxycarbonyl, aryl-substituted lower alkoxycarbonyl, for example optionally substituted benzyloxycarbonyl or pyridylmethoxycarbonyl, (hydroxyl or lower alkoxy) -substituted lower alkoxycarbonyl, for example pivaloyloxymethoxycarbonyl, (hydroxy, lower alkanoyloxy or lower alkoxy) -substituted lower alkoxymethoxycarbonyl, bicycloalkoxycarbonyl-substituted lower alkoxycarbonyl, for example bicyclo- [2,2,1] -heptyloxycarbonyl-substit low alkoxycarbonyl, in particular bicyclo [2,2,1] heptyloxycarbonyl-substituted methoxy, for example bornyloxycarbonylmethoxycarbonyl, 3-phthalideoxy carbonyl, (lower alkyl, lower alkoxy, halogen) -substituted 3-phthalidoxycarbonyl, lower alkoxycarbonyloxy-lower alkoxycarbonyl, for example 1- (methoxy- or ethoxycarbonyloxy) -ethoxycarbonyl, aryloxycarbonyl, for example phenoxycarbonyl or phenoxycarbonyl, which is advantageously in the ortho position by carboxy or Lower alkoxycarbonyl is substituted.

Salts are preferably pharmaceutically usable salts, in particular metal or ammonium salts of the compounds of formula I mentioned, which have a free carboxy group, especially alkali metal or alkaline earth metal salts, e.g. Sodium, potassium, magnesium or calcium salts; primarily slightly crystallizing ammonium salts derived from ammonia or organic amines, e.g. Mono-, di- or tri-lower (alkyl or cycloalkyl) amines, tri (hydroxy-lower alkyl) amines, lower alkylene diamines or (hydroxy-lower alkyl or aryl-lower alkyl) lower alkylammonium hydroxides, e.g. Methylamine, diethylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, tris (hydroxymethyl) aminomethane or benzyltrimethylammonium hydroxide. The compounds of formula I mentioned form acid addition salts. These are preferably prepared with those inorganic or organic acids which give pharmaceutically usable acid addition salts. Such acids are e.g. strong mineral acids such as hydrohalic acids e.g. Hydrochloric or hydrobromic acid, sulfuric, phosphoric, nitric or perchloric acid; or organic acids, especially aliphatic or aromatic carboxylic or sulfonic acids, e.g. Ant, vinegar, pripion, amber, glycol, milk, apple, wine, glucon, lemon, maleic, fumaric, pyrux, phenylacetic, benzoic, 4-aminobenzoic, Anthranil, 4-hydroxybenzoic, salicyl, 4-aminosalicyl, pamoe, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid; or other acidic organic substances, e.g. the ascorbic acid.

For isolation or purification, pharmaceutically unsuitable salts can also be used. Only the pharmaceutically usable, non-toxic salts are used therapeutically, which is why they are preferred.

The compounds of the invention show valuable pharmacological properties, e.g. cardiovascular effects by selectively inhibiting thromboxane release in mammals. This inhibition occurs due to the selective lowering of the thromboxane synthetase level. The compounds are therefore useful in the treatment of such diseases in mammals that respond to inhibition of thromboxane synthetase. Such diseases are primarily cardiovascular disorders such as thrombosis, arteriosclerosis, coronary spasms, cerebral ischemic attacks, migraines and other vascular headaches, myocardial infarction, angina pectoris and hypertension.

These effects can be demonstrated by in vitro experiments or in vivo animal experiments, preferably on mammals, e.g. on guinea pigs, mice, rats, cats, dogs or monkeys. The compounds mentioned can be administered enterally or parenterally, preferably orally or subcutaneously, intravenously or intraperitoneally, e.g. by means of gelatin capsules or in the form of starch-containing suspensions or aqueous solutions. The dose used can range from about 0.01 to 100 mg / kg / day, preferably from about 0.05 to 50 mg / kg / day and in particular from about 0.1 to 25 mg / kg / day.

• 14 C-Arachidonsäure wird mit einem Enzymgemisch-Präparat, bestehend aus solubilisierter und partiell gereinigter Prostaglandin-cyclooxygenase von Schaf-Samenblasen und aus einem rohen Mikrosomen-Präparat von Thromboxan-Synthetase, das von lysierten menschlichen Blutplättchen stammt, inkubiert. Die Testverbindung (gelöst in einem Puffer, oder, falls nötig, in wenig Aethanol) wird zu dem Inkubationsmedium gegeben. Am Ende der Inkubationsperiode (30 Minuten) wird das Prostaglandin E₂ (PGE₂) durch Hinzufügen von Natriumborhydrid zu einem Gemisch aus Prostaglandin F_Za und F₂ß [PGF₂α+ß] reduziert. Die radioaktiven Produkte und das überschüssige Substrat werden mit Essigsäureäthylester extrahiert und der Extrakt zur Trockene eingedampft. Der Rückstand wird in Aceton gelöst, auf Dünnschichtplatten aufgetragen und mit dem Lösungsmittelsystem Toluol/Aceton/Eisessig [100:100:3 (Volumen)] chromatographiert. Die radioaktiven Zonen werden lokalisiert. Die Zonen von Thromboxan B (TxB₂) und PGF a+ß werden in Szintillationsröhrchen für Flüssigkeiten übertragen und gezählt. Der Quotient aus den Zahlenwerten von TxB₂ und PGF₂a+ß wird für jede Konzentration der Testverbindung berechnet und daraus die IC₅₀-Werte graphisch ermittelt. Dieser Wert entspricht der Konzentration an Testverbindung, bei welcher der Quotient TxB₂/PGF₂α+β auf 50% des Kontrollwertes reduziert wird.

The in vitro inhibition of the thromboxane synthetase enzyme can be analogous to the method of Sun [Biochem. Biophys. Res. Comm. 74, 1432 (1977)]. The test procedure is carried out as follows:

• 14 C-arachidonic acid is made with an enzyme mixture preparation consisting of solubilized and partially purified prostaglandin cyclooxygenase from sheep seminal vesicles and a raw microsome Incubated preparation of thromboxane synthetase derived from lysed human platelets. The test compound (dissolved in a buffer or, if necessary, in a little ethanol) is added to the incubation medium. At the end of the incubation period (30 minutes), prostaglandin E ₂ (PGE ₂ ) is reduced by adding sodium borohydride to a mixture of prostaglandin F _Z a and F ₂ ß [PGF ₂ α + ß]. The radioactive products and the excess substrate are extracted with ethyl acetate and the extract is evaporated to dryness. The residue is dissolved in acetone, applied to thin-layer plates and chromatographed with the solvent system toluene / acetone / glacial acetic acid [100: 100: 3 (volume)]. The radioactive zones are located. The zones of thromboxane B (TxB ₂ ) and PGF a + ß are transferred and counted in scintillation tubes for liquids. The quotient of the numerical values of TxB ₂ and PGF ₂ a + ß is calculated for each concentration of the test compound and the IC ₅₀ values are determined graphically. This value corresponds to the concentration of test compound at which the quotient TxB ₂ / PGF ₂ α + β is reduced to 50% of the control value.

• Lyophilisierte Samenblasen-Mikrosomen von Schafen werden als Prostaglandin-synthetisierendes Enzympräparat verwendet. Es wird die Umwandlung von 14 C-Arachidonsäure in PGE₂ gemessen. Die Testverbindungen (gelöst in einem Puffer, oder, wenn nötig, in wenig Aethanol) werden zu dem Inkubationsgemisch gegeben. Die Prostaglandine werden extrahiert und durch Dünnschichtchromatographie aufgetrennt. Die Platten werden überprüft, die dem PGE₂ entsprechenden radioaktiven Zonen in Szintillationsröhrchen für Flüssigkeiten übertragen und ihre Radioaktivität gezählt. Zur Bestimmung der IC₅₀-Werte für die Hemmung wird graphisch die Konzentration an Testverbindung ermittelt, bei welcher die Menge des synthetisierten PGE₂ um 50% reduziert wird.

The in vitro effect of the compounds on prostaglandin cyclooxygenase is measured according to a modification of the method by Takeguchi et al. [Biochemistry 10, 2372 (1971)]. The test procedure is as follows:

• Lyophilized sheep's seminal vesicle microsomes are used as a prostaglandin-synthesizing enzyme preparation. The conversion of 14 C-arachidonic acid into PGE _{2 is} measured. The test compounds (dissolved in a buffer or, if necessary, in a little ethanol) are added to the incubation mixture. The prostaglandins are extracted and separated by thin layer chromatography. The plates are checked, the radioactive zones corresponding to the PGE ₂ are transferred into scintillation tubes for liquids and their radioactivity is counted. To determine the IC ₅₀ values for the inhibition, the concentration of test compound is determined graphically, at which the amount of PGE ₂ synthesized is reduced by 50%.

• ¹⁴C-Arachidonsäure wird mit einem Enzymgemisch inkubiert, das aus solubilisierter und partiell gereinigter Prostaglandin-cyclooxygenase von Schaf-Samenblasen sowie aus roher PGI₂-Synthetase besteht, die in Form einer Mikrosomen-Fraktion, gewonnen aus Rinderaorten, vorliegt.

The in vitro effect on prostacyclin (PGI2) synthase is determined analogously to the method of Sun et al., Prostaglandins 14, 1055 (1977). The test procedure is as follows:

• ¹⁴ C-arachidonic acid is incubated with an enzyme mixture consisting of solubilized and partially purified prostaglandin cyclooxygenase from sheep seminal vesicles and crude PGI ₂ synthetase, which is in the form of a microsome fraction obtained from bovine aortas.

The test compound (dissolved in a buffer or, if necessary, in a little ethanol) is added to the incubation medium. The reaction mixture is incubated in 100 mM Tris HCl (pH 7.5) at 37 ° C. for 30 minutes, acidified to pH 3 and extracted with ethyl acetate. The extract is evaporated to dryness, the residue is dissolved in acetone, applied to thin-layer plates and mixed with that described by Sun et al. chromatographed solvent system described. The radioactive zones are located with a detector. The zones corresponding to 6-keto-PGF ₁ α (a stable end product of the prostacyclin biotransformation) and PGE ₂ are transferred and counted in scintillation tubes for liquids. The quotient of the numerical values of 6-keto-PGF ₁ a and PGE ₂ is calculated for each concentration of the test compound used and the IC ₅₀ values of the inhibition are determined graphically therefrom. This value corresponds to the concentration of test compound at which the quotient 6-keto-PGF ₁ α / PGE _{2 is} reduced to 50% of the control value.

• Ratten werden mit der Testsubstanz oder einem Trägermaterial behandelt; nach 2 h wir ihnen lonophor A 23187 (0,5 mg/kg) intravenös injiziert. Zwei Minuten nach der Ionophor-Verabreichung wird den Tieren für die Analyse Blut entnommen. Eine bestimmte Einzelmenge jeder Plasmaprobe wird mittels Radioimmunoassay auf Thromboxan B₂, und eine weitere auf 6-Keto-PGF_la, die stabilen Metaboliten des Thromboxans A₂ bzw. des Prostacyclins (PGI₂), untersucht.

The inhibition of thromboxane synthesis and the reduction of the thromboxane plasma level is achieved in vivo by administration of the test compound to rats [analogous to that of Tai et al. in Anual. Biochem. 87, 343 (1978) and methods described by Salmon in Prostaglandins 15, 383 (1978)] as follows:

• Rats are treated with the test substance or a carrier material; after 2 h we were injected with ionophore A 23187 (0.5 mg / kg) intravenously. Two minutes after ionophore administration, blood is drawn from the animals for analysis. A certain individual amount of each plasma sample is examined by radioimmunoassay for thromboxane B ₂ , and another for 6-keto-PGF _l a, the stable metabolites of thromboxane A ₂ and prostacyclin (PGI ₂ ).

The compounds of formula I are very potent and selective thromboxane synthetase inhibitors. At effective dose levels and above, neither the beneficial prostacyclin synthetase nor the prostaglandin cyclooxygenase enzyme system is significantly inhibited. Surprisingly, the prostacyclin level is significantly increased.

At an oral dose of 0.10 mg / kg or less, compounds of the invention lower the plasma concentration of thromboxane B _{2 in} rats by over 50%; at the same time, an increase in the plasma level of prostacyclin is surprisingly observed.

Because of the advantageous properties mentioned, the compounds of the invention are very valuable as specific therapeutic agents for mammals, including humans.

The usefulness of the compounds of the invention in thromboembolism can be seen from the fact that compounds of the invention abolish platelet aggregation in different ways, as well as thrombocytopenia. A useful antithrombotic effect e.g. indicated by the prolongation of the bleeding time in the rat. Compounds of the present invention prolong this bleeding time at an oral dose of approximately 10 mg / kg or less.

In addition to the pharmaceutically usable salts mentioned above, all pharmacological precursors of the carboxylic acids according to the invention, so-called "prodrugs", form, for example, their pharmaceutically usable esters and amides which can be converted into the carboxylic acids mentioned by solvolysis or under physiological conditions, a further subject of this invention.

Such esters are preferably e.g. straight-chain or branched lower alkyl esters which may be unsubstituted or appropriately substituted, such as pivaloyloxymethyl, 2-diethylaminoethyl, bornyloxycarbonylmethyl, a-carboxyethyl or suitably esterified a-carboxyethyl esters and the like, which can be prepared in a manner known per se .

The amides mentioned are preferably e.g. simple primary or secondary amides and those derived from amino acids or their derivatives, e.g. derived from alanine or phenylalanine.

• A für Alkylen mit 4 bis 12 Kohlenstoffatomen, Nieder-(alkylen- phenylen, alkylen-thio-phenylen oder alkylen-oxy-phenylen) mit 7 bis 10 Kohlenstoffatomen steht;
• B Carboxy, Niederalkoxycarbonyl, Carbamoyl, Cyan, Hydroxycarbamoyl, 5-Tetrazolyl oder Hydroxymethyl bedeutet; und ihre Salze, insbesondere ihre pharmazeutisch verwendbaren Salze.

Preferred compounds of the formula I are those in which R _{1 is} hydrogen or lower alkyl, Ar is in each case unsubstituted or substituted by lower alkyl 3-pyridyl or 1-imidazolyl, R ₂ and R ₃ independently of one another are hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxyl, lower alkoxy or Lower alkylthio, or R ₂ and R ₃ together, on adjacent carbon atoms, are lower alkylenedioxy;

• A represents alkylene with 4 to 12 carbon atoms, lower (alkylene-phenylene, alkylene-thiophenylene or alkylene-oxy-phenylene) with 7 to 10 carbon atoms;
• B represents carboxy, lower alkoxycarbonyl, carbamoyl, cyano, hydroxycarbamoyl, 5-tetrazolyl or hydroxymethyl; and their salts, especially their pharmaceutically acceptable salts.

Furthermore, the compounds of the formula I are preferred in which the radical R _{2 is} attached in the 5-position of the indole nucleus and R _{3 is} hydrogen.

The compounds of the formula I in which B is carboxy, lower alkoxycarbonyl, carbamoyl, 5-tetrazolyl or hydroxycarbamoyl are particularly preferred.

Compounds of the formula I are particularly preferred in which A is alkylene with 4 to 10 carbon atoms, lower alkylene-phenylene with 7 to 10 carbon atoms, lower alkylene-thiophenylene with 7 to 10 carbon atoms or lower alkylene-oxy-phenylene with 7 to 10 carbon atoms , B is carboxy or lower alkoxycarbonyl, Ar is 3-pyridyl or 1-imidazolyl and R ₂ and R _{3 are} independently hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy, lower alkylthio or lower alkoxy; and their salts, especially their pharmaceutically acceptable salts.

Compounds of the formula I are preferred in which A is alkylene having 4 to 8 carbon atoms.

worin R₁ ¹ Wasserstoff oder Niederalkyl bedeutet, R₂' und R₃' unabhängig voneinander für Wasserstoff, Niederalkyl, Halogen, Trifluormethyl, Hydroxy, Niederalkylthio oder Niederalkoxy stehen, oder R₂' und R₃' zusammen, an benachbarten Kohlenstoffatomen, Methylendioxy bedeuten, m für eine ganze Zahl von 4 bis 12 steht und R₄ Hydroxy, Niederalkoxy oder Amino bedeutet; und ihre Salze, insbesondere ihre pharmazeutisch verwendbaren Salze.Compounds of the formula II are of particular interest

wherein R ₁ ^{1 is} hydrogen or lower alkyl, R ₂ 'and R ₃ ' independently of one another are hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy, lower alkylthio or lower alkoxy, or R ₂ 'and R ₃ ' together, on adjacent carbon atoms, are methylenedioxy , m is an integer from 4 to 12 and R _{4 is} hydroxy, lower alkoxy or amino; and their salts, especially their pharmaceutically acceptable salts.

Furthermore, the compounds of formula II are preferred in which R ₃ 'is hydrogen.

Also preferred are those compounds of the formula II in which R ₁ 'is methyl, ethyl or propyl, R ₂ ' is hydrogen, methyl, chlorine, fluorine, trifluoromethyl, hydroxyl, methylthio or methoxy, R ₃ 'is hydrogen, m is a is an integer from 4 to 8 and R _{4 is} hydroxy, ethoxy, methoxy or amino; and their salts, especially their pharmaceutically acceptable salts.

Compounds of the formula II in which R ₁ 'is hydrogen or lower alkyl, R ₂ ' is hydrogen or halogen, R ₃ 'is hydrogen, m is an integer from 4 to 8 and R _{4 is} hydroxyl, lower alkoxy or amino means, and their salts, especially their pharmaceutically acceptable salts.

First and foremost, the compounds of the formula II are preferred in which R 'is hydrogen or methyl, R ₂ ' is hydrogen or chlorine, R ₃ 'is hydrogen, m is 5 and R is hydroxy, and their salts, in particular their pharmaceuticals usable salts.

worin R₁' Wasserstoff oder Niederalkyl bedeutet, R₂' und R₃' unabhängig voneinander für Wasserstoff, Niederalkyl, Halogen, Trifluormethyl, Hydroxy, Niederalkylthio oder Niederalkoxy stehen, oder R₂' und R₃' zusammen, an benachbarten Kohlenstoffatomen, Methylendioxy bedeuten, m für eine ganze Zahl von 3 bis 12 steht und R₄ Hydroxy, Niederalkoxy oder Amino bedeutet, und ihre Salze, insbesondere ihre pharmazeutisch verwendbaren Salze.Compounds of the formula III are also preferred

wherein R ₁ 'is hydrogen or lower alkyl, R ₂ ' and R ₃ 'independently of one another are hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy, lower alkylthio or lower alkoxy, or R ₂ ' and R ₃ 'together, on adjacent carbon atoms, are methylenedioxy , m is an integer from 3 to 12 and R _{4 is} hydroxy, lower alkoxy or amino, and their salts, especially their pharmaceutically acceptable salts.

Compounds of the formula III are preferred in which R ₃ 'is hydrogen.

Particularly preferred are compounds of the formula III in which R is methyl, ethyl or propyl, R ₂ 'is hydrogen, methyl, chlorine, fluorine, trifluoromethyl, hydroxy, methylthio or methoxy, R ₃ ' is hydrogen, m is an integer from 3 to 8 and R _{4 is} hydroxy, ethoxy, methoxy or amino, and their salts, in particular their pharmaceutically acceptable salts.

Compounds of the formula III in which R ₁ 'is hydrogen or lower alkyl, R ₂ ' is hydrogen or halogen, R ₃ 'is hydrogen, m is an integer from 4 to 8 and R _{4 is} hydroxy, lower alkoxy or are very particularly preferred Amino means, and their salts, especially their pharmaceutically acceptable salts.

Those compounds of formula III are preferred in which R ₁ 'is hydrogen or methyl, R ₂ ' is hydrogen or chlorine, R ₃ 'is hydrogen, m is 5 and R _{4 is} hydroxy, and their salts, in particular their pharmaceutically acceptable salts.

Above all, the compounds of the formula I described in the examples and their pharmaceutically usable salts are preferred.

• 1) eine Verbindung der Formel IV
  
  worin R₁, R₂, R₃, A und B die unter Formel I angegebene Bedeutung haben und X für Halogen steht, mit einer Verbindung der Formel Ar-H oder einem reaktiven metallierten Derivat davon, worin Ar die unter Formel I angegebene Bedeutung hat, umsetzt, und, falls gewünscht, eine erhaltene Verbindung der Formel I, worin R₁ Wasserstoff ist, mit einem Alkylierungsmittel in eine Verbindung der Formel I überführt, worin R₁ Niederalkyl bedeutet, oder
• 2) eine Verbindung der Formel V
  
  worin R₁, R₂, R₃ und Ar die unter Formel I angegebene Bedeutung haben, als reaktives metallorganisches Derivat mit einem reaktiven funktionellen Derivat einer Verbindung der Formel VI
  
  worin A und B die unter Formel I angegebene Bedeutung haben, umsetzt, und, falls gewünscht, eine erhaltene Verbindung der Formel I, worin R₁ Wasserstoff ist, mit einem Alkylierungsmittel in eine Verbindung der Formel I umsetzt, worin R₁ Niederalkyl ist, oder
• 3) eine Verbindung der Formel VII
  
  worin R₁, R₂, R₃, A und B die unter Formel I angegebene Bedeutung haben und Ar für unsubstituiertes oder wie unter Formel I angegeben substituiertes 3-Pyridyl steht, ringschliesst, oder
• 4) eine Verbindung der Formel VIII
  
  worin Ar, R₁, R₂, R_3' A und B die unter Formel I angegebene Bedeutung haben, cyclisiert, oder
• 5) zur Herstellung einer Verbindung der Formel I, worin A z.B. Alkenylen bedeutet, unter den Bedingungen einer Wittig-Reaktion eine Verbindung der Formel Va
  
  die einem 3-Formylderivat einer Verbindung der Formel V entspricht, mit dem Ylid einer Verbindung der Formel XII
  
  worin B die unter Formel I angegebene Bedeutung hat, A' z.B. Alkylen wie oben für A in Verbindungen der Formel I definiert, jedoch mit um 1 Kohlenstoffatom verkürzter Kettenlänge, ist und R einen Dialkylphosphono- oder Triarylphosphonium-Rest bedeutet, umsetzt oder
• 6) zur Herstellung einer Verbindung der Formel I, worin z.B. A Niederalkyl-(thio oder oxy)-niederalkylen oder Niederalkylen-(thio oder oxy)-phenylen bedeutet, eine Verbindung der Formel Vb
  
  worin Ar, R₁ ,R₂ und R₃ die unter Formel I angegebene Bedeutung haben und R₆ und R₇ jeweils Niederalkyl bedeuten - also ein 3-(disubstituiertes Aminomethyl)-Derivat einer Verbindung der Formel V - mit z.B. einer Verbindung der Formel XIII
  
  oder einem reaktiven Alkalimetall- oder Ammonium-Derivat davon, worin B wie unter Formel I angegeben definiert ist, R₅' Hydroxy oder Thiol bedeutet und A" z.B. für Niederalkylen oder Phenylen steht; oder mit z.B. einem Lacton oder Thiolacton einer Verbindung der Formel XIII, worin R₅' Hydroxy oder Thiol bedeutet, A" Niederalkylen ist und B für Carboxy steht, umsetzt, oder
• 7) eine Verbindung der Formel la
  
  worin A, Ar, R₁, R₂ und R₃ die unter Formel I angegebene Bedeutung haben und C eine von B verschiedene und in B überführbare Gruppe bedeutet, gegebenenfalls unter Verlängerung der Kette A im Rahmen ihrer Definition, oder eine Verbindung der Formel I^* oder Ia^*, die derjenigen der Formel I beziehungsweise la gleicht, worin jedoch abweichend A für Alkylen mit 1 oder 2 Kohlenstoffatomen steht, unter Verlängerung der Alkylenkette A zu Alkylen mit einer solchen Zahl von Kohlenstoffatomen wie sie unter Formel 1 definiert ist, in eine Verbindung der Formel I umwandelt; wobei störende reaktionsfähige Gruppen im Molekül gegebenenfalls vorübergehend geschützt sind, und/oder, wenn erwünscht, eine erhaltene Verbindung der Formel I in eine andere Verbindung der Erfindung umwandelt, und/oder, wenn erwünscht, eine erhaltene freie Verbindung der Formel I in ein Salz oder ein erhaltenes Salz in die freie Verbindung oder in ein anderes Salz überführt, und/oder, wenn erwünscht, ein erhaltenes Gemisch von Isomeren oder Racematen in die einzelnen Isomeren oder Racemate auftrennt, und/oder, wenn erwünscht, erhaltene Racemate in die optischen Antipoden aufspaltet.

The compounds of the present invention are prepared by methods known per se, preferably by

• 1) a compound of formula IV
  
  wherein R ₁ , R ₂ , R ₃ , A and B have the meaning given under formula I and X represents halogen, with a compound of formula Ar-H or a reactive metalated derivative thereof, wherein Ar has the meaning given under formula I. , and, if desired, converting a compound of formula I, wherein R _{1 is} hydrogen, with an alkylating agent into a compound of formula I, wherein R _{1 is} lower alkyl, or
• 2) a compound of formula V
  
  wherein R ₁ , R ₂ , R ₃ and Ar have the meaning given under formula I, as a reactive organometallic derivative with a reactive functional derivative of a compound of formula VI
  
  in which A and B have the meaning given under formula I, and, if desired, converting a compound of formula I obtained, in which R _{1 is} hydrogen, with an alkylating agent into a compound of formula I in which R _{1 is} lower alkyl, or
• 3) a compound of formula VII
  
  in which R ₁ , R ₂ , R ₃ , A and B have the meaning given under formula I and Ar is unsubstituted or substituted as indicated under formula I, ring-closes, or
• 4) a compound of formula VIII
  
  wherein Ar, R ₁ , R ₂ , R _{3 '} A and B have the meaning given under formula I, cyclized, or
• 5) for the preparation of a compound of formula I, in which A is, for example, alkenylene, under the conditions of a Wittig reaction, a compound of formula Va
  
  which corresponds to a 3-formyl derivative of a compound of formula V, with the ylide of a compound of formula XII
  
  in which B has the meaning given under formula I, A 'is, for example, alkylene as defined above for A in compounds of the formula I, but with a chain length reduced by 1 carbon atom, and R is a dialkylphosphono- or triarylphosphonium radical, is reacted or
• 6) for the preparation of a compound of the formula I, in which, for example, A is lower alkyl (thio or oxy) lower alkylene or lower alkylene (thio or oxy) phenylene, a compound of the formula Vb
  
  wherein Ar, R ₁ , R ₂ and R _{3 have} the meaning given under formula I and R ₆ and R ₇ each represent lower alkyl - that is a 3- (disubstituted aminomethyl) derivative of a compound of the formula V - with, for example, a compound of the formula XIII
  
  or a reactive alkali metal or ammonium derivative thereof, in which B is as defined under formula I, R ₅ 'is hydroxy or thiol and A "is, for example, lower alkylene or phenylene; or with, for example, a lactone or thiolactone of a compound of the formula XIII , wherein R ₅ 'is hydroxy or thiol, A "is lower alkylene and B is carboxy, or
• 7) a compound of formula la
  
  wherein A, Ar, R ₁ , R ₂ and R _{3 have} the meaning given under formula I and C is a group different from B and convertible into B, optionally with the chain A being extended within the scope of its definition, or a compound of the formula I. ^* or Ia ^* , which is similar to that of formula I or la, but in which A is alkylene with 1 or 2 carbon atoms, with extension of the alkylene chain A to alkylene with a number of carbon atoms as defined under formula 1, in one Converts compound of formula I; interfering reactive groups in the molecule are optionally temporarily protected, and / or, if desired, a compound of the formula I obtained in converts another compound of the invention and / or, if desired, converts an obtained free compound of formula I into a salt or an obtained salt into the free compound or another salt, and / or, if desired, an obtained mixture of Separates isomers or racemates into the individual isomers or racemates, and / or, if desired, splits racemates obtained into the optical antipodes.

worin R_2' R₃₁ A und B die oben angegebene Bedeutung haben, mit einem Halogen, vorzugsweise Brom, in einem inerten Lösungsmittel wie z.B. Dioxan, vorteilhaft bei Raumtemperatur umsetzt.The compounds of formula IV necessary for carrying out process 1) are prepared, for example, preferably in situ by adding a compound of formula IVa

wherein R _{2 '} R ₃₁ A and B have the meaning given above, with a halogen, preferably bromine, in an inert solvent such as dioxane, advantageously at room temperature.

The subsequent reaction with a compound of formula Ar-H or a reactive organometallic derivative thereof, e.g. an alkali metal derivative, is carried out in a temperature range from 0 ° to 100 ° C., advantageously at room temperature.

Process 1) is particularly advantageous for the preparation of compounds of the formula I in which Ar is unsubstituted or 1-imidazolyl which is substituted by lower alkyl, a compound of the formula Ar-H corresponding to unsubstituted or substituted on one of the carbon atoms with lower alkyl imidazole. The indoles of the formula IVa used as starting materials are either known or, if new, are prepared by methods known per se.

To carry out process 2), the compounds of the formula V are first converted into reactive organometallic derivatives, e.g. in alkali metal or halogen magnesium (Grignard) derivatives by means of an agent suitable for metalation, e.g. a Grignard reagent, an alkali metal base or a quaternary ammonium base. Preferably the compounds of formula V are converted in situ to the reactive organometallic intermediates using a reactive metallizing agent, preferably with a molar equivalent of e.g. a strong alkali metal base, e.g. Lithium diisopropylamide, sodium hydride, potassium tert-butoxide, a Grignard reagent, e.g. a lower alkyl magnesium halide such as methyl or ethyl magnesium bromide in an inert solvent such as e.g. Dimethylformamide, diethyl ether or tetrahydrofuran, in a temperature range from -50 ° to + 75 ° C, preferably from -25 ° and + 50 ° C. The reaction of the resulting reactive organometallic compounds of the formula V with a reactive esterified derivative of a compound of the formula VI is carried out in a temperature range from approximately -25 ° to + 50 ° C., preferably in a range from 0 ° to 30 ° C. In cases where B represents carboxy, carbamoyl, hydroxycarbamoyl or mono-lower alkylcarbamoyl, one or more further molar equivalents of the metalating agent are required.

The intermediates of formula V are known (for example IJS patent 3,468,894; J. Chem. Soc. 1955, 2865; Bull. Soc. Chim. France 1969, 4154) or are prepared analogously to the known ones, for example by reaction of the corresponding ones optionally substituted phenylhydrazines with ketones of the formula ArCOCH ₃ in the presence of a condensing agent, for example ethanolic HC1 solution or polyphosphoric acid, according to the known Fischer indole synthesis.

The starting compounds of formula VI are known or, if new, are prepared by conventional methods, e.g. according to the procedures outlined in U.S. Patent 4,256,757 and British Patent Application 2,016,452 A.

The ring closure of the starting material of formula VII according to process 3) is carried out according to the well-known Fischer indole synthesis, which is described, for example, thermally in "Heterocyclic Compounds, Indoles Part I" (editor: WJ Houlihan) pp. 232-317 or preferably in the presence of an acidic condensing agent. In the latter case it is preferred, preferably operates in the presence of hydrogen halides, eg ethanolic hydrogen chloride, or polyphosphoric acid optionally in an inert solvent at temperatures between about 50 ^* and 100 ° C.

worin R₁' R2 und R₃ die oben für Verbindungen der Formel I angegebene Bedeutung haben, vorteilhaft in Gegenwart eines sauren Katalysators, hergestellt.The hydrazone intermediates of the formula VII are - in isolated form or preferably in situ - by condensation of a ketone of the formula ArCOCH ₂ -AB, in which Ar, A and B have the meaning given above for compounds of the formula 1, with a hydrazine of the formula IX

wherein R ₁ 'R2 and R _{3 have} the meaning given above for compounds of the formula I, advantageously in the presence of an acid catalyst.

worin R1, R2 und R₃ die oben angegebene Bedeutung haben, und nachfolgende Reduktion der N-Nitroso-Derivate, z.B. mit Zink in Essigsäure oder nach anderen an sich bekannten Methoden, hergestellt.The hydrazine starting materials of the formula IX are known or are preferably obtained, for example, by nitrosation of appropriately substituted anilines of the formula X.

wherein R1, R2 and R _{3 have} the meaning given above, and subsequent reduction of the N-nitroso derivatives, for example with zinc in acetic acid or by other methods known per se.

The cyclization according to process 4) is carried out under the conditions of the indole synthesis according to Madelung, as described in "Heterocyclic Compounds, Indoles Part I" (publisher W.J. Houlihan) pp. 385-396. The intramolecular cyclization is preferably carried out in the presence of a strong base, e.g. Sodium ethoxide, sodium amide or potassium tert-butoxide, advantageously at elevated temperature, e.g. at about 300 ° C, or in an inert high-boiling solvent, e.g. Tetrahydronaphthalene.

worin A, B, R₁, R₂ und R₃ die oben angegebene Bedeutung haben, mit einer Verbindung der Formel ArCOOH, worin Ar vorzugsweise unsubstituiertes oder wie oben definiert substituiertes 3-Pyridyl bedeutet, oder einem reaktiven funktionellen Derivat davon, erhalten.The starting materials of the formula VIII, in which Ar preferably denotes unsubstituted or substituted 3-pyridyl as indicated above, are obtained by acylation of substituted anilines of the formula XI

wherein A, B, R ₁ , R ₂ and R _{3 have} the meaning given above, with a compound of the formula ArCOOH, in which Ar is preferably unsubstituted or as defined above substituted 3-pyridyl, or a reactive functional derivative thereof.

The starting compounds of the formula Va required for carrying out process 5) can be e.g. by preparing a compound of formula V under the conditions of the Vilsmeier-Haack reaction with an N, N-disubstituted formamide, e.g. with dimethylformamide, in the presence of phosphorus oxychloride.

Dialkylphosphono means, for example, diethylphosphono _. and a triarylphosphonium residue is, for example, triphenylphosphonium.

The starting compounds of the formula Vb required for carrying out process 6) can e.g. by obtaining a compound of formula V under the conditions of the Mannich reaction e.g. with formaldehyde and a secondary amine, e.g. Dimethylamine, implemented.

The conversion of a compound of the formula Ia, in which C differs from B, according to process 7) into a compound of the formula I, and the optional conversion of a product of the formula I obtained into another compound of this invention are carried out according to known chemical methods Methods and / or as described here.

Convertible groups C are preferably trialkoxymethyl, esterified hydroxymethyl, etherified hydroxymethyl, halomethyl, 2-oxazolinyl, dihydro-2-oxazolinyl, lower alkanoyloxymethyl, acetyl, methyl, carboxycarbonyl, trihalogenoacetyl, di-lower alkoxymethyl, alkylenedioxymethyl ester, vinyl, carboxy, carboxyl, alkynyl .

The intermediates of formula Ia are e.g. in strict analogy to the processes 1) to 6) or as described here, in each case using chemical methods known per se.

• Reaktive funktionelle Derivate eines Alkohols der Formel VI sind z.B. solche, in denen die Hydroxygruppe mit einer starken anorganischen oder organischen Säure, vor allem mit einer Halogenwasserstoffsäure, z.B. Chlorwasserstoff-, Bromwasserstoff-oder Jodwasserstoffsäure, einer aliphatischen oder aromatischen Sulfonsäure, z.B. Methansulfon- oder p-Toluolsulfonsäure, verestert ist. Diese Verbindungen werden in an sich bekannter Weise hergestellt.

The individual definitions in the previously described methods have the following meaning:

• Reactive functional derivatives of an alcohol of the formula VI are, for example, those in which the hydroxyl group contains a strong inorganic or organic acid, especially a hydrohalic acid, for example hydrochloric acid, hydrobromic acid or hydroiodic acid, an aliphatic or aromatic sulfonic acid, for example methanesulfonic acid or p -Toluenesulfonic acid, is esterified. These compounds are produced in a manner known per se.

Trialkoxymethyl preferably means tri (lower alkoxy) methyl, especially triethoxy or trimethoxy methyl.

Etherified hydroxymethyl preferably means tertiary lower alkoxymethyl, lower alkoxy alkoxymethyl, e.g. Methoxymethoxymethyl, 2-oxa- or 2-thiacycloalkoxymethyl, especially 2-tetrahydropyranyloxymethyl.

Esterified hydroxymethyl preferably means lower alkanoyloxymethyl, advantageously acetoxymethyl, lower alkylsulfonyloxymethyl, e.g. Methylsulfonyloxymethyl, or arylsulfonyloxymethyl, e.g. p-tolylsulfonyloxymethyl.

Halogenomethyl stands in particular for chloromethyl, but can also be bromomethyl or iodomethyl.

An alkali metal preferably means lithium, but can also be potassium or sodium.

The conversion of compounds of the formula 1a into compounds of the formula I and the conversion of compounds of the formula I into another compound of the invention are carried out according to chemical methods known per se.

Intermediates of formula la in which C is halomethyl may preferably be mixed with a metal cyanide, e.g. Potassium cyanide, are implemented in a manner known per se. This gives compounds of the formula I in which the chain is extended by one carbon atom and B is cyan. These can in turn be converted into compounds of the formula I, in which B is carboxy, lower alkoxycarbonyl or carbamoyl, by methods known per se.

Thus compounds of formula I in which B is cyan (nitriles) in compounds of formula I in which B is carboxy can be obtained by hydrolysis with inorganic acids, e.g. with hydrohalic acids such as hydrochloric acid or sulfuric acid in aqueous solution, or preferably by hydrolysis with aqueous alkali metal hydroxides, e.g. Potassium hydroxide to be converted at reflux temperature.

The conversion of the nitriles mentioned into compounds of the formula I, in which B is lower alkoxycarbonyl, is preferably first carried out by treatment with a lower alkanol, e.g. anhydrous ethanol, in the presence of a strong acid, e.g. Hydrochloric acid, preferably under reflux, and subsequent careful hydrolysis with water.

The conversion of the nitriles mentioned into compounds of the formula I in which B is carbamoyl is preferably carried out by treatment with an alkali metal hydroxide, e.g. dilute sodium hydroxide solution, and hydrogen peroxide, preferably at room temperature.

Intermediates of the formula Ia in which C is halomethyl, for example chloromethyl, can be used in compounds of the formula I in which B is carboxy and extends the chain by 2 carbon atoms is converted by first treating them, for example, with a di-lower alkyl malonate, for example diethyl malonate, in the presence of a base, for example potassium carbonate or sodium ethoxide, in a solvent such as dimethylformamide, preferably at a temperature between 50 ^* and 100 ° C. The resulting substituted di-lower alkyl malonates are then preferably hydrolyzed with an aqueous base, for example dilute sodium hydroxide solution, to give the corresponding malonic acid, which is decarboxylated under standard conditions, for example by heating in xylene, to give a compound of the formula I in which B is carboxy. If the malonic acid di-lower alkyl ester is replaced by a cyanoacetic acid lower alkyl ester, the corresponding compounds of formula I are obtained, in which B is cyano.

Compounds of the invention in which A is a straight-chain or branched alkenylene radical with a terminal double bond can also be prepared from the intermediates of the formula Ia, in which C is halomethyl. For example, these intermediates can first be treated with a lower alkyl ester of a- (aryl- or alkyl) -thioacetic acid, for example a- (phenylthio) -acetic acid ethyl ester, in the presence of a strong base, for example sodium hydride. The subsequent oxidation of the a-arylthio- or a-alkylthio-substituted ester obtained to the corresponding a-arylsulfinyl or a-alkylsulfinyl ester, for example with sodium periodate, followed by an elimination initiated by heat, for example by heating in xylene, gives a compound of general formula I (an α, β-unsaturated ester) in which A is alkenylene and B is, for example, lower alkoxycarbonyl. The chain is extended by two carbon atoms at the same time. The same conversion can also be carried out using, for example, ethyl a- (phenylseleno) acetic acid, as described in J. Am. Chem. Soc. 95, 6137 (1973). The compounds of the formula Ia in which C is halomethyl can also first be converted into the corresponding carboxyaldehydes, for example with dimethyl sulfoxide in the presence of triethylamine and silver tetrafluoroborate, or with chromium trioxide and pyridine in methylene chloride. The following Wittig condensation eg with Trimethylphosphonoacetate or (triphenylphosphoranylidene) acetic acid ethyl ester also gives the a, 8-unsaturated esters mentioned above.

Compounds of formula I, wherein B is lower alkoxycarbonyl, can be reacted with ammonia, mono- or di-lower alkylamines, e.g. Methylamine or dimethylamine, in an inert solvent, e.g. a lower alkanol such as butanol, optionally at elevated temperatures, to compounds of the formula I in which B denotes unsubstituted, mono- or di-lower alkyl-substituted carbamoyl.

Compounds of formula I in which A represents a straight-chain or branched alkenylene radical with a terminal double bond, e.g. α, β-unsaturated esters can also be prepared from the corresponding α, β-saturated compounds by treatment e.g. with phenylselenyl chloride in the presence of a strong base according to the method described in J. Am. Chem. Soc. 95, 6137 (1973) can be obtained.

The conversion of compounds of formula I in which B is lower alkoxycarbonyl, cyano, unsubstituted, mono- or di-lower alkyl-substituted carbamoyl into compounds of formula I in which B is carboxy is advantageously accomplished by hydrolysis with inorganic acids, e.g. with hydrohalic acids or sulfuric acid, or with aqueous alkalis, preferably with alkali metal hydroxides, e.g. Lithium or sodium hydroxide.

Compounds of formula I in which B represents carboxy or lower alkoxycarbonyl can be mixed with simple or complex light metal hydrides, e.g. with lithium aluminum hydride, alan or diborane, to compounds of the formula I in which B represents hydroxymethyl, are reduced. These alcohols can also be obtained by appropriate solvolysis of intermediates of formula Ia, where C is halomethyl, by treatment e.g. with an alkali metal hydroxide, e.g. Lithium or sodium hydroxide can be obtained.

The alcohols mentioned above can in turn be converted into compounds of the formula I in which B is carboxy using conventional oxidizing agents, preferably pyridine dichromate in dimethylformamide at room temperature.

Free carboxylic acids can be mixed with lower alkanols, e.g. Ethanol in the presence of a strong acid, e.g. Sulfuric acid, preferably at elevated temperature, or with diazo-lower alkanes, e.g. Diazomethane in a solvent, e.g. Diethyl ether, preferably at room temperature, to the corresponding esters, namely to those compounds of the formula I in which B is lower alkoxycarbonyl.

Furthermore, the free carboxylic acids can be treated by treating one of their reactive intermediates, e.g. an acyl halide, such as an acid chloride or mixed anhydride, e.g. one derived from a lower alkyl halocarbonic acid e.g. Ethyl chloroformate is derived, with ammonia, mono- or di-lower alkylamines, in an inert solvent, e.g. Methylene chloride, preferably in the presence of a basic catalyst, e.g. Pyridine, in compounds of formula I, in which B represents unsubstituted, mono- or di-lower alkyl-substituted carbamoyl, are converted.

Compounds of formula I, wherein B is mono-lower alkyl-carbamoyl, can be converted into compounds of formula I, in which B is di-lower alkyl-carbamoyl, by treatment with a strong base, e.g. Sodium hydride followed by an alkylating agent, e.g. a lower alkyl halide, in an inert solvent, e.g. Dimethylformamide, are transferred.

Compounds of the formula I in which A is a straight-chain or branched alkynylene or alkenylene radical can also be obtained by catalytic hydrogenation, preferably under neutral conditions, for example with a palladium catalyst at atmospheric Pressure, in an inert solvent, for example ethanol, into compounds of the formula I in which A represents straight-chain or branched alkylene.

Carboxaldehydes, namely compounds of the formula I in which B is formyl, can be obtained by oxidation of compounds of the formulas I or Ia in which B or C are hydroxymethyl or halomethyl, e.g. with dimethyl sulfoxide and a catalyst, e.g. a mixture of triethylamine and silver tetrafluoroborate, or with chromium trioxide and pyridine or with other suitable oxidizing agents known per se. The carboxaldehydes mentioned can be converted into the corresponding acetals, i.e. Compounds of formula Ia where C is di (lower alkoxy) methyl or alkylenedioxymethyl, e.g. the dimethyl acetal, by acid catalyzed condensation with an alcohol, e.g. Methanol.

Compounds of formula I in which B is carboxy can be converted to compounds of formula I in which B is carboxy and chain A contains one more carbon atom by the well known Arndt-Eistert synthesis. In particular, one can use a reactive functional derivative of the carboxylic acid used as the starting material, e.g. an acid chloride, with diazomethane e.g. treat in diethyl ether to give a compound of formula Ia wherein C is diazoacetyl. After treatment e.g. with silver oxide the carboxylic acid of formula I is obtained, in which chain A is extended by one carbon atom.

A particular embodiment of process 7) relates to the preparation of compounds of the formula I in which B is carboxy. It consists in converting the group C into carboxy in a compound of the formula Ia in which C is a radical which can be converted into the carboxy group, optionally with the chain A being extended within the scope of its definition.

Residues which can be converted into a carboxy group are e.g. esterified carboxy, anhydrous carboxy including corresponding asymmetric and internal anhydrides, amidated carboxy, cyano, amidine structures, including cyclic amidines, e.g. 5-tetrazolyl, imino ethers including cyclic imino ethers such as e.g. unsubstituted or substituted by lower alkyl 2-oxazolinyl or dihydro-2-oxazolinyl radicals, furthermore methyl, hydroxymethyl, etherified hydroxymethyl, lower alkanoyloxymethyl, trialkoxymethyl, acetyl, trihaloacetyl, halomethyl, carboxycarbonyl (-COCOOH), formyl, di-lower alkoxymethyl Vinyl, ethynyl, or diazoacetyl. Simultaneously with the conversion of C into the carboxy group, the chain A can be extended within the scope of its definition.

Esterified carboxy is preferably carboxy in the form of its lower alkyl esters, e.g. of the methyl, ethyl, n or iso (propyl or butyl) ester. Also in the form of substituted lower alkyl esters, e.g. the m-amino, w-monomethylamino or ω-dimethylamino, a-carboxy or α-ethoxycarbonyl (ethyl, propyl or butyl) ester. Other esters are aryl lower alkyl esters, e.g. Benzyl, (methyl, methoxy, chlorine) substituted benzyl and pyridylmethyl esters; Lower alkanoyloxy lower alkyl esters, e.g. Pivaloyloxymethyl ester; unsubstituted and substituted by methyl, methoxy or chlorine 3-phthalidyl esters derived from the corresponding 3-hydroxy-phthalides (hydroxy, lower alkanoyloxy, lower alkoxy) -substituted lower alkoxy methyl esters, e.g. β- (hydroxy, acetyloxy, methoxy) ethoxymethyl ester; Bicycloalkyloxycarbonyl lower alkyl esters, e.g. those derived from bicyclic monoterpenoid alcohols, e.g. unsubstituted or substituted by lower alkyl bicyclo [2,2,1] heptyloxycarbonyl lower alkyl esters, advantageously bornyloxycarbonyl methyl esters; or halogen-substituted lower alkyl esters, e.g. Trichloroethyl or iodoethyl esters are derived.

Amidated carboxy is preferably carboxy in the form of its unsubstituted amides, N-mono- or N, N-di-lower alkylamides, e.g. Mono- or dimethylamides; in the form of tertiary amides, e.g. may be derived from pyrrolidine, piperidine or morpholine; further a-lower alkoxycarbonyl- or a-carboxy-substituted lower alkylamides, e.g. Mono-N-ethoxycarbonylmethyl) amides and mono-N- (carboxymethyl) amides; a-lower alkoxycarbonyl- or a-carboxy-substituted aryl-lower alkylamides, e.g. Ethoxycarbonyl- or carboxy-substituted phenylethylamides; Amino-lower alkylamides, e.g. ß-Amino-ethylamides and ß- (Benzyloxycarbonyl-amino) -ethylamides.

The conversion into the carboxy group is carried out according to methods known per se, e.g. as described here and in the examples, e.g. Solvolytic, such as hydrolytic or acidolytic as described above, or reductive in the case of esterified carboxy groups. For example, 2,2,2-trichloroethyl or 2-iodoethyl ester by reduction e.g. converted into the carboxylic acid with zinc and a carboxylic acid in the presence of water. Benzyl esters or nitro-benzyl esters can be obtained by catalytic hydrogenation or by hydrogenation with chemical reducing agents, e.g. Sodium dithionite or zinc and a carboxylic acid, e.g. Acetic acid to be converted into the carboxy group. Furthermore, tert-butyl esters e.g. can also be cleaved with trifluoroacetic acid.

During the reduction of the radical C, an alkenylene or alkynylene chain A can be converted into the corresponding alkylene chain at the same time.

Furthermore, compounds of the formula Ia in which C is acetyl can be cleaved oxidatively to the corresponding compounds of the formula I in which B is carboxy. For this purpose, the acetyl compound is first converted into a compound of formula Ia, in which C is trihaloacetyl, e.g. Tribromo or triiodoacetyl means transferred, e.g. by treatment with sodium hypobromite, and subsequently e.g. split with an aqueous base, such as sodium hydroxide solution.

Starting materials of the formula Ia in which C is acetyl can be prepared from compounds of the formula Ia in which C is halomethyl by treatment with a lower alkyl acetoacetate, e.g. Ethyl acetoacetate, in the presence of a base, e.g. Sodium hydride, and subsequent hydrolysis with a strong base, e.g. with aqueous sodium hydroxide solution.

The compounds mentioned can also be obtained by condensation of a compound of the formula la in which C is cyano, e.g. with a Grignard or other organometallic reagent, e.g. Methyl magnesium bromide, can be produced under standard conditions.

Starting materials of the formula Ia in which C is carboxycarbonyl (-COCOOH) can be converted by thermal treatment or by means of oxidation into compounds of the formula I in which B is carboxy. The starting material is used at elevated temperature, e.g. about 200 ° C, heated in the presence of glass powder, or e.g. with hydrogen peroxide in the presence of a base, e.g. Sodium hydroxide treated.

The starting materials of formula Ia, in which C denotes carboxycarbonyl, can e.g. by condensation of a compound of formula Ia in which C is halomethyl, e.g. with 2-ethoxycarbonyl-1,3-dithiane, subsequent oxidative hydrolysis, e.g. with N-bromosuccinimide in aqueous acetone, and finally treatment with e.g. dilute aqueous sodium hydroxide solution can be obtained.

Compounds of formula Ia, wherein C is formyl, di-lower alkoxy-methyl or alkylenedioxymethyl - the latter corresponds to formyl protected as acetal - e.g. Dimethylacetal, means e.g. with silver nitrate, pyridinium dichromate or ozone to the corresponding compounds of formula I, wherein B is carboxy, are oxidized.

Compounds of formula Ia where C is vinyl can be converted to compounds of formula I where B is carboxy. For this purpose, they are first converted by ozonolysis into compounds of the formula I, in which B is formyl, which in turn can be oxidized in a manner known per se to give compounds of the formula I, in which B is carboxy.

Starting materials of the formula Ia, in which C is vinyl, can also be treated with nickel carbonyl and carbon monoxide under elevated pressure, to give compounds of the formula I in which B is carboxy and chain A bears a double bond in the vicinity of the carboxy group.

Compounds of formula Ia, wherein C is ethynyl, can be mixed with a strong base, e.g. Butyllithium, treated at a temperature of -70 ° to + 50 ° C, then with carbon dioxide or a lower alkyl haloformate, e.g. Chloroformic acid ethyl ester, condensed and then hydrolyzed. Compounds of the formula I are obtained in which B is carboxy and chain A contains a triple bond adjacent to the carboxy group.

Compounds of formula la, wherein C is halomethyl, can be incorporated into the corresponding organometallic intermediates, e.g. Copper or magnesium derivatives, can be converted according to methods known per se.

The reaction of, for example, an organic magnesium (Grignard) reagent obtained, for example a compound of the formula Ia in which C is converted to CH ₂ MgCl, with carbon dioxide gives a compound of the formula I in which B is carboxy and the chain around a carbon atom is extended.

The reaction of the aforementioned Grignard reagent e.g. with a lower alkyl haloacetate, e.g. Ethyl bromoacetate, and subsequent hydrolysis gives a compound of formula I, wherein B is carboxy and the chain is extended by 2 carbon atoms.

Said Grignard reagent can be used in the presence of a copper I halide, e.g. Copper-I-chloride, with an α, β-unsaturated acid, e.g. be condensed with propiolic acid or acrylic acid to give a compound of formula I wherein B is carboxy and the chain is extended by 3 carbon atoms.

Compounds of formula Ia wherein C is halomethyl, e.g. are condensed with the 3-lithio derivative of propiolic acid (prepared in situ from propiolic acid and, for example, lithium diisopropylamide), giving a compound of the formula I in which A contains terminal alkynylene, B is carboxy and the chain has 3 carbon atoms is extended.

Compounds of formula I, wherein A is lower alkylene and B is hydroxymethyl or, in particular, a reactive functional derivative thereof, can preferably with a lower alkanol (or lower alkanethiol), or a phenol (or thiophenol), which are each appropriately substituted by B. in the presence of a strong base. Compounds of the formula I are obtained in which A denotes lower alkylene- (thio or oxy) phenylene or lower alkylene- (thio or oxy) lower alkylene.

If any of the intermediates mentioned contain interfering reactive groups, for example carboxy, hydroxyl or amino groups, they can preferably be protected temporarily, at each stage, by easily removable protective groups. The purpose of introducing protecting groups is to protect functional groups from undesirable reactions with reactants and thereby prevent them from being split off or converted into derivatives. On the other hand, it can happen that in the presence of unprotected functional groups, reactants are undesirably consumed or bound by reaction with the former and are therefore not available for the reaction actually intended. The choice of protective group for a particular reaction depends on various points, namely the type of functional group to be protected, the structure and stability of the molecule on which the functional group is located, and the reaction conditions. Protecting groups which meet these conditions, their introduction and removal are known and described per se, for example in JFW McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London, New York 1973. For example, carboxy groups can be protected as esters, for example as unsubstituted or substituted lower alkyl esters, such as the methyl or benzyl ester, it being possible to split off such ester groups easily under mild conditions, in particular alkaline conditions. Amino or hydroxy protective groups which can be split off again under gentle conditions are, for example, acyl radicals, such as, for example, lower alkanoyl optionally substituted by halogen, for example formyl or trichloroacetyl, or organic silyl groups, for example tri-lower alkylsilyl, such as, for example, trimethylsilyl. In a compound of the formula I or in any intermediate product which contains one or more functional groups in protected form, for example protected carboxy, amino or hydroxy, the latter can be released in a manner known per se, for example by solvolysis, for example hydrolysis.

The above-mentioned reactions are carried out according to methods known per se, in the presence or absence of diluents, preferably those which are inert to the reagents and which dissolve them, catalysts, condensation agents or other agents mentioned above, and / or an inert atmosphere, with cooling , at room temperature or at elevated temperature, preferably at the boiling point of the solvent used, at normal or elevated pressure. The preferred solvents, catalysts and reaction conditions are disclosed in the accompanying examples.

The invention also relates to modifications of the present process, according to which an intermediate product obtained at any stage of the process is used as the starting material and the remaining process steps are carried out, or the process is terminated at any stage, or according to which a starting material is formed under the reaction conditions, or wherein one or more of the starting materials is used in the form of a salt or an optically pure antipode.

In the process of the present invention, those starting materials are preferably used which lead to the compounds described above as being particularly valuable.

The invention also relates to new starting materials and processes for their production.

Depending on the choice of starting materials and the process used, the new compounds can be in the form of one of the possible isomers or as isomer mixtures. Thus, depending on the presence of a double bond and the number of asymmetric carbon atoms, e.g. pure optical isomers, such as antipodes, or mixtures of optical isomers, e.g. Racemates, mixtures of diastereomers, mixtures of racemates or mixtures of geometric isomers. The aforementioned possible isomers and their mixtures belong to the scope of the present invention. Certain specific isomers may be preferred.

Mixtures of diastereomers, mixtures of racemates or geometric isomers obtained can be converted into the pure isomers, diasteromers, racemates or geometric isomers in a manner known per se on the basis of the physicochemical differences of their components. by chromatography and / or fractional crystallization.

Racemates obtained can be further incorporated into the optical antipodes in a manner known per se, e.g. by reacting an acidic end product with an optically active base which forms salts with the racemic acid. These salts can e.g. be separated into the diastereomeric salts by fractional crystallization. The optically active acid antipodes can be released from the latter by acidification. Basic racemic products can be processed in an analogous manner, e.g. by separating their diastereomeric salts with an optically active acid and releasing the optically active basic end products with an ordinary base. Racemic products of the invention can thus be cleaved into their optical antipodes, e.g. by fractional crystallization of d- or 1- (tartrates, mandelates, camphorsulfonates, or of d- or l- (a-methylbenzylamine, cinchonidine, cinchonine, quinine, quinidine, ephedrine, dehydroabietylamine, brucine or strychine) salts. Preferably from two antipodes of the more potent isolated.

Finally, the compounds of the invention can be obtained in free form or as salts. A free base obtained can be converted into the corresponding acid addition salt, preferably with acids which give therapeutically usable acid addition salts, or with anion exchangers. Salts obtained can be added to the corresponding free bases e.g. by treatment with a stronger base such as a metal or ammonium hydroxide or a basic salt, e.g. an alkali metal hydroxide or carbonate, or with a cation exchanger. A compound of the formula I in which B denotes carboxy can also be converted into the corresponding metal or ammonium salts in this way. These or other salts, e.g. the picrates, can also be used in the purification of free bases obtained. The bases are converted into their salts, the salts are separated off and the bases are released from the salts.

As a result of the close relationship between the new compounds in free form and in the form of their salts, in the preceding and the following, free compounds and salts are to be understood as meaningful and appropriate, if appropriate, also the corresponding salts or free compounds.

The compounds and their salts can also be obtained in the form of their hydrates or include other solvents used for the crystallization.

The pharmaceutical preparations according to the invention are those which are suitable for enteral, e.g. oral or rectal, and parenteral administration to mammals, including humans. These preparations contain an effective dose of at least one pharmacologically active compound of formula I, or one of its pharmaceutically acceptable salts, alone or in combination with one or more pharmaceutically acceptable carrier materials.

The pharmacologically active compounds of the present invention can be used for the production of pharmaceutical preparations which contain an effective amount of the active substance together or in a mixture with carriers which are suitable for enteral or parenteral administration. Tablets or gelatin capsules are preferably used which contain the active ingredient together with diluents, for example lactose, dextrose, cane sugar, mannitol, sorbitol, cellulose and / or glycine, and lubricants, for example silica, talc, stearic acid or its salts, such as magnesium or calcium stearate. and / or polyethylene glycol; Tablets also contain binders, for example magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and / or polyvinyl pyrrolidone, and, if desired, disintegrants, for example starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures and / or adsorbents, colors, flavors and sweeteners. Injectable preparations are preferably isotonic aqueous solutions or suspensions, and suppositories primarily Fat emulsions or suspensions. The pharmaceutical preparations can be sterilized and / or contain auxiliaries, for example preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical preparations, which, if desired, can contain further pharmacologically valuable substances, are produced in a manner known per se, for example by means of conventional mixing, granulating or coating processes, and contain about 0.1% to about 75%, in particular about 1 X to about 50 Z, of the active ingredient. Single doses for mammals weighing approximately 50 to 70 kg can contain approximately 10 to 100 mg of the active ingredient.

The following examples serve to illustrate the invention and are not to be construed as limiting its scope. Temperatures are given in degrees Celsius, and parts are by weight. Unless otherwise defined, the evaporation of solvents is carried out under reduced pressure, preferably between approximately 20 and 130 mbar.

Example 1: A mixture of 10.32 g of phenylhydrazine hydrochloride and 16.8 g of 7-nicotinoylheptane carboxylic acid in 750 ml of ethanol is heated at the reflux temperature for 6 hours. After cooling in an ice-water bath, 250 ml of about 2N ethanolic hydrogen chloride are added and the mixture is heated under reflux for 16 h. The mixture is filtered and the filtrate is concentrated under reduced pressure. The crude product is treated with petroleum ether and recrystallized from ethanol / ether; 3- [5- (Aethoxycarbonyl) pentyl] -2- (3-pyridyl) indole hydrochloride, mp. 145 to 150 °, is obtained.

• Zu einer Suspension von 16 g 50-proz. Natriumhydrid in 450 ml Aether werden tropfenweise 92,2 g Korksäure-diäthylester und 27,3 ml (30,2 g) Nikotinsäure-äthylester bei Raumtemperatur und unter Stickstoff zugegeben. Das Reaktionsgemisch wird bei Rückflusstemperatur über Nacht erhitzt und, nach Abkühlen, mit 400 ml Eiswasser versetzt. Die Aetherphase wird abgetrennt und verworfen, die wässerige Phase mit 1 n Salzsäure auf pH 5 eingestellt und mit Aether extrahiert (3 x 250 ml). Die Aetherphase wird getrocknet und konzentriert; man erhält 7-Aethoxycarbonyl-7-nikotinoylheptancarbonsäure-äthylester als Oel. Eine Lösung dieses Esters in 300 ml 1 m Schwefelsäure wird 12 Stunden bei Rückflusstemperatur erhitzt. Die Reaktionslösung wird in einem Eisbad abgekühlt und auf pH 4,5 bis 5,0 mit gesättigter Natriumhydrogencarbonatlösung eingestellt. Ein weisser Feststoff wird gesammelt und nach dem Waschen mit Wasser und dem Trocknen an der Luft aus Aethanol umkristallisiert; man erhält 7-Nikotinoylheptancarbonsäure, Fp. 113 bis 115°.

The starting compound is made as follows:

• To a suspension of 16 g 50 percent. Sodium hydride in 450 ml of ether are added dropwise 92.2 g of diethyl corkate and 27.3 ml (30.2 g) of nicotinic acid ethyl ester at room temperature and under nitrogen. The reaction mixture is heated at reflux temperature overnight and, after cooling, with 400 ml of ice water transferred. The ether phase is separated off and discarded, the aqueous phase is adjusted to pH 5 with 1N hydrochloric acid and extracted with ether (3 × 250 ml). The ether phase is dried and concentrated; 7-Aethoxycarbonyl-7-nicotinoylheptanecarboxylic acid ethyl ester is obtained as an oil. A solution of this ester in 300 ml of 1 M sulfuric acid is heated at the reflux temperature for 12 hours. The reaction solution is cooled in an ice bath and adjusted to pH 4.5 to 5.0 with saturated sodium bicarbonate solution. A white solid is collected and, after washing with water and air drying, recrystallized from ethanol; 7-nicotinoylheptane carboxylic acid is obtained, mp. 113 to 115 °.

Example 2: A solution of 7.46 g of 3- [5- (ethoxycarbonyl) pentyl] -2- (3-pyridyl) indole in 2N aqueous hydrochloric acid (275 ml) is heated under reflux for 20 h. The hot reaction mixture is filtered; the filtrate gives yellow crystals on cooling, which are collected by filtration and dried; 3- (5-Carboxypentyl) -2- (3-pyridyl) indole hydrochloride, mp. 220 to 222 °, is obtained.

An aqueous solution of 10.5 g of 3- (5-carboxypentyl) -2- (3-pyridyl) indole hydrochloride is neutralized to a pH of about 7 with saturated sodium bicarbonate solution and extracted with ether. The ether extract is dried and concentrated in vacuo; 3- (5-carboxypentyl) -2- (3-pyridyl) indole is obtained.

Example 3: A solution of 8.8 g of 3- (5-carboxypentyl) -2- (3-pyridyl) indole is added dropwise to a suspension of 1.2 g of sodium hydride (60% in mineral oil) in 50 ml of dimethylformamide under nitrogen protection placed in 50 ml of dimethylformamide at room temperature. After the addition, the mixture is stirred for 0.5 h, cooled to 0 to 5 ° and treated with 1.62 ml of methyl iodide. The mixture is stirred overnight, poured into ice water and acidified with 1N hydrochloric acid. After extraction with ether, the aqueous phase is brought to a pH of 9 to 10 with saturated sodium hydrogen adjusted carbonate solution and extracted twice with 300 ml of ether. The ether phase is washed with sodium chloride solution, dried (MgS0 ₄ ) and concentrated to an oil.

A solution of the residue in 300 ml of 2N hydrochloric acid is heated at the reflux temperature for 2 h. After concentration in vacuo, a sodium hydrogen carbonate solution is added to adjust the pH to 5.5 to 6.5. The gummy solid that forms is extracted with methylene chloride. The organic phase is dried and evaporated and the residue is crystallized from acetonitrile; 3- (5-Carboxypentyl) -1-methyl-2- (3-pyridyl) indole, mp 128 to 130 °, is obtained ^.

Example 4: a) According to Example 1, condensation of p-methoxyphenylhydrazine with 7-nicotinoylheptanecarboxylic acid gives 2- (3-pyridyi) -3- [5- (ethoxycarbonyl) pentyl] -5-methoxyindoi hydrochloride, mp. 152 bis 154 °.

b) The following hydrolysis according to Example 2 gives 2- (3-pyridyl) -3- (5-carboxypentyl) -5-methoxyindole, mp. 185 to 187 °.

Example 5: A solution of 1.5 g of 2- (3-pyridyl) -3- [5- (ethoxycarbonyl) pentyl] -5-methoxyindole in 15 ml of 48 percent. Hydrobromic acid is heated at reflux temperature for 2.5 h. The reaction solution is cooled and neutralized to pH 6 to 7 with sodium hydrogen carbonate solution and then extracted with ethyl acetate. The organic extract is dried (MgS0 ₄ ) _' filtered and concentrated to a solid which is recrystallized from acetonitrile; 5-Hydroxy-2- (3-pyridyl) -3- (5-carboxypentyl) indole, mp. 185 to 187 °, is obtained.

Example 6: A mixture of 9.60 g of 7-nicotinoylheptane carboxylic acid and 7.34 g of 4-chlorophenylhydrazine in 100 ml of ethanol is stirred and heated under reflux under nitrogen protection overnight. The reaction mixture is concentrated in vacuo to a rubber-like product which is suspended in 100 ml of ethanol, treated with 40 ml of 6N ethanolic hydrogen chloride and under nitrogen for 22 hours is heated under reflux. The suspension is cooled and an additional 50 ml of 6N ethanolic hydrogen chloride are added. Refluxing is resumed and continued for about 20 hours. The suspension is cooled in an ice-water bath and filtered. The filtrate is concentrated in vacuo to a partially solid residue which is treated with ether / ethanol (10: 1); the yellow solid formed is collected; 3- [5- (Aethoxycarbonyl) pentyl] -5-chloro-2- (3-pyridyl) indole hydrochloride, mp 141 to 145 °, is obtained.

The hydrolysis with 2 N aqueous hydrochloric acid according to Example 2 gives 3- (5-carboxypentyl) -5-chloro-2- (3-pyridyl) indole hydrochloride, mp. 255 to 257 °.

Example 7: A solution of 2.12 g of 5-chloro-3- [5- (ethoxycarbonyl) pentyl] -2- (3-) is added dropwise to a suspension of sodium hydride in 10 ml of dry dimethylformamide with stirring and nitrogen protection at 0 °. pyridyl) indole in dimethylformamide. After the addition is complete, the orange suspension is stirred at 0 ° for 0.5 h. 0.42 ml of iodomethane is added to the suspension. The suspension is allowed to warm to room temperature. After stirring overnight at room temperature, the reaction mixture is poured into water (80 ml) and extracted with ether (3 x 50 ml). The ether extract is washed with water and a saturated sodium chloride solution, dried (MgS0 ₄ ), filtered and concentrated in vacuo; 5-chloro-3- [5- (ethoxycarbonyl) pentyl] -1-methyl-2- (3-pyridyl) indole is obtained.

Example 8: A mixture of 1.0 g of 5-chloro-3- [5- (ethoxycarbonyl) pentyl] -1-methyl-2- (3-pyridyl) indole in 20 ml of 2N aqueous hydrochloric acid is stirred overnight and heated under reflux. The mixture is cooled; the solid formed is collected and dried in vacuo; 3- (5-Carboxypentyl) -5-chloro-l-methyl-2- (3-pyridyl) indole hydrochloride, mp. 186 to 189 °, is obtained.

Example 9:

a) A solution of 3- (4-cyanobenzyl) -2- (3-pyridyl) indole (5.8 g) in 100 ml of a 1: 1 mixture of 20 percent. aqueous hydrochloric acid and glacial acetic acid is heated under reflux for 20 h. After cooling, the solution is poured into ice water (100 ml) and the pH is adjusted to 4.5 to 5 with saturated sodium bicarbonate solution. The resulting precipitate is extracted with ethyl acetate; the ethyl acetate extract is washed with water and evaporated to dryness; 3- (4-Carboxybenzyl) -2- (3-pyridyl) indole is obtained.

• Zu 30 ml einer 2 m Aethylmagnesiumbromidlösung in Tetrahydrofuran wird unter Stickstoffschutz bei 0 bis 5° tropfenweise im Verlauf von 20 min eine Lösung von 10,0 g 2-(3-Pyridyl)-indol in 60 ml Tetrahydrofuran gegeben. Das Reaktionsgemisch wird 0,5 h bei 0 bis 5° gerührt, dann tropfenweise mit 9,8 g p-Cyanbenzylbromid in 50 ml Tetrahydrofuran versetzt. Man rührt 1 h bei 0 bis 10°, 0,5 h bei Raumtemperatur und giesst dann das Reaktionsgemisch in Eiswasser (600 ml). Der entstandene Feststoff wird gesammelt, getrocknet, mit Petroläther gewaschen und in Aether (500 ml) wieder aufgelöst. Die Aetherlösung wird zuerst mit Wasser, dann mit gesättigter Natriumhydrogencarbonatlösung gewaschen, über MgS0₄ getrocknet, mit Kohle behandelt und filtriert. Nach dem Eindampfen des Aetherextrakts zur Trockene und anschliessender Reinigung erhält man 3-(4-Cyanbenzyl)-2-(3-pyridyl)-indol.

The starting nitrile is produced as follows:

• A solution of 10.0 g of 2- (3-pyridyl) indole in 60 ml of tetrahydrofuran is added dropwise over a period of 20 minutes to 30 ml of a 2 M ethylmagnesium bromide solution in tetrahydrofuran under nitrogen protection at 0 to 5 °. The reaction mixture is stirred at 0 to 5 ° for 0.5 h, then 9.8 g of p-cyanobenzyl bromide in 50 ml of tetrahydrofuran are added dropwise. The mixture is stirred for 1 h at 0 to 10 °, 0.5 h at room temperature and then poured into ice water (600 ml). The resulting solid is collected, dried, washed with petroleum ether and redissolved in ether (500 ml). The ether solution is washed first with water, then with saturated sodium bicarbonate solution, dried over MgSO ₄ , treated with charcoal and filtered. After evaporation of the ether extract to dryness and subsequent purification, 3- (4-cyanobenzyl) -2- (3-pyridyl) indole is obtained.

b) 3- (4-Carboxybenzyl) -5-chloro-2- (3-pyridyl) indole is prepared accordingly.

Example 10:

a) To a suspension of 0.49 g of lithium aluminum hydride in 50 ml of anhydrous tetrahydrofuran, a solution of 4.09 g of 3- (5-ethoxycarbonylpentyl) -5-chloro-l-methyl-2- (3- pyridyl) indole in 30 ml of anhydrous tetrahydrofuran. When the addition is complete, the suspension is stirred for 1 hour at room temperature and with 50 ml of saturated ammonium chloride solution added. The reaction mixture is left to stand at room temperature overnight, then the organic phase is separated off. The aqueous phase is filtered to remove the salts and extracted with ethyl acetate (2 x 50 ml). The combined organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by treatment with hexane / ether and dissolved in ethanol. The solution is mixed with ethanolic hydrochloric acid until an acidic reaction and diluted with anhydrous ether to crystallize the product. 5-Chloro-3- (6-hydroxyhexyl) -1-methyl-2- (3-pyridyl) indole hydrochloride is obtained.

b) 3- (6-Hydroxyhexyl) -1-methyl-2- (3-pyridyl) indole is prepared accordingly.

Example 11: To a suspension of 1.52 g of 3- (5-carboxypentyl) -5-chloro-l-methyl-2- (3-pyridyl) indole in 50 ml of toluene, dropwise at room temperature, 0.31 ml at room temperature Thionyl chloride added. The resulting mixture is heated under reflux for 1 h. A further 0.10 ml of thionyl chloride is added to the solution and the mixture is stirred at room temperature overnight. The resulting suspension is evaporated to dryness; 3- (5-Chlorocarbonylpentyl) -5-chloro-l-methyl-2- (3-pyridyl) indole is obtained. A suspension of this acid chloride in 20 ml of concentrated ammonia solution is stirred at room temperature overnight. The resulting solid is filtered off; 3- (5-Carbamoylpentyl) -5-chloro-l-methyl-2- (3-pyridyl) indole is obtained.

Example 12: A solution of 4 g of 3- (5-ethoxycarbonylpentyl) -1-methyl-2- (3-pyridyl) indole in 40 ml of n-butanol is saturated with methylamine and heated, in a steam bath in a pressure bottle for three days. The reaction mixture is evaporated to dryness and the product is crystallized from diethyl ether; 3- [5- (N-Methylcarbamoyl) pentyl] -1-methyl-2- (3-pyridyl) indole is obtained.

Example 13: A solution of 50 mg of 3- (5-carbamoylpentyl) -5-chloro-1-methyl-2- (3-pyridyl) indole in 1 ml of 6N hydrochloric acid is heated at the reflux temperature for 3 hours. The hydrochloride (salt) precipitates on cooling. The suspension is evaporated to dryness and the residue is made alkaline with saturated sodium bicarbonate solution. This solution is washed with ether and neutralized to pH 6 to 7 with 2N hydrochloric acid. After extraction with methylene chloride, 3- (5-carboxypentyl) -5-chloro-l-methyl-2- (3-pyridyl) indole is obtained, which by treatment with 2N hydrochloric acid in the corresponding hydrochloride, mp. 186 to 189 ° is transferred.

Example 14: A solution of 10.0 g of 2- (3-pyridyl) indole in 60 ml of tetrahydrofuran is added dropwise under nitrogen at 0 to 5 ° over 30 minutes to 30 ml of a 2 M ethylmagnesium bromide solution in tetrahdrofuran. The mixture is stirred at 0 to 5 ° for 0.5 h, then 17.6 g of 1-tetrahydropyranyloxy-8-bromo-octane in 50 ml of tetrahydrofuran are added dropwise. The reaction mixture is stirred at 0 to 10 ° for 1 h and at room temperature for 0.5 h, poured into ice water and extracted with ether. The ether extract is washed with water, dried over MgSO ₄ and evaporated to dryness. The residue is dissolved in 100 ml of 3N hydrochloric acid, the resulting mixture is left to stand at room temperature for 0.5 h, washed with ether, made alkaline with 3N aqueous sodium hydroxide solution and extracted with methylene chloride. The methylene chloride solution is evaporated to dryness; 3- (8-hydroxyoctyl) -2- (3-pyridyl) indole is obtained.

Example 15: A solution of 4.0 g of 2- (3-pyridyl) indole in 20 ml of tetrahydrofuran is added dropwise over a period of 20 minutes under nitrogen protection at 0 to 5 ° to 12 ml of a 2 M ethylmagnesium bromide solution in tetrahydrofuran. The mixture is stirred at 0 to 5 ° for 0.5 h and then with a solution of 5.06 g of ethyl p- (2-bromo-ethoxy) benzoate [for the preparation see US Pat. No. 2,790,825 (1957)] in 30 ml of tetrahydrofuran are added. The suspension is stirred at 0 to 10 ° for 1 h and at room temperature for 0.5 h, in Poured ice water and extracted with ether. The ether extract is separated off, dried over magnesium sulfate and concentrated; 3- [2- (4-Aethoxycarbonylphenoxy) ethyl] -2- (3-pyridyl) indole is obtained.

Example 16: A mixture of 4.5 g of 3- [2- (4-ethoxycarbonylphenoxy) ethyl] -2- (3-pyridyl) indole in 220 ml of 2N hydrochloric acid is heated under reflux for 6 h. After cooling, the solution is made alkaline with 3N sodium hydroxide solution and extracted with ethyl acetate. The basic solution is filtered and brought to pH 6 to 7 with 3N hydrochloric acid. The solid is collected and dried; 3- [2- (4-Carboxyphenoxy) ethyl] -2- (3-pyridyl) indole is obtained.

Example 17: A solution of 5.9 g of ethyl p-mercaptobenzoate (prepared according to J. Chem. Soc. 1963, pages 1947 to 1954) in 30 ml of dimethylformamide is added dropwise to a slurry of 1.55 g of 50 percent. Sodium hydride (dispersion in mineral oil) in 30 ml of dimethylformamide. This mixture is stirred at room temperature for 0.5 h under a nitrogen atmosphere and added dropwise to a solution of 9.78 g of 3- (2-methylsulfonyloxyethyl) -2- (3-pyridyl) indole in 60 ml of dimethylformamide at -10 °. This mixture is stirred at room temperature overnight, poured into 1 liter of ice water and then extracted a few times with ether. The ether extract is washed with water, dried over magnesium sulfate and evaporated in vacuo; 3- [2- (4-Aethoxycarbonylphenylthio) ethyl] -2- (3-pyridyl) indole is obtained.

• Zu 10,0 g 3-(2-Aethoxycarbonyläthyl)-2-(3-pyridyl)-indol in 400 ml trockenem Tetrahydrofuran werden bei O° 60 ml einer 1 m Lithiumaluminiumhydridlösung in Tetrahydrofuran gegeben. Das Gemisch wird bei Raumtemperatur 1 h gerührt, dann in einem Eisbad gekühlt und nacheinander mit 2,26 ml Wasser, 2,26 ml einer 15-proz. Natriumhydroxidlösung und 6,78 ml Wasser versetzt. Das Gemisch wird filtriert und im Vakuum eingeengt; der Rückstand wird in Aether gelöst, mit gesättigter Natriumhydrogencarbonatlösung gewaschen, über Magnesiumsulfat getrocknet und im Vakuum eingeengt; man erhält 3-(2-Hydroxyäthyl)-2-(3-pyridyl)-indol.

The starting compound can be made as follows:

• 60 ml of a 1 M lithium aluminum hydride solution in tetrahydrofuran are added to 10.0 g of 3- (2-ethoxycarbonylethyl) -2- (3-pyridyl) indole in 400 ml of dry tetrahydrofuran at 0 °. The mixture is stirred at room temperature for 1 h, then cooled in an ice bath and successively with 2.26 ml of water, 2.26 ml of a 15 percent. Sodium hydroxide solution and 6.78 ml of water are added. The mixture is filtered and concentrated in vacuo; the residue is in ether dissolved, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo; 3- (2-Hydroxyethyl) -2- (3-pyridyl) indole is obtained.

Methanesulfonyl chloride (2.50 ml) is added dropwise to a solution of 7.5 g of 3- (2-hydroxyethyl) -2- (3-pyridyl) indole and 10.0 ml of triethylamine in 150 ml of methylene chloride at -10 °. This mixture is stirred at room temperature for 0.5 h and poured into 600 ml of ice water. The resulting slurry is extracted with methylene chloride; the extract is washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo; 3- (2-Methylsulfonyloxyethyl) -2- (3-pyridyl) indole is obtained.

Example 18: A mixture of 6.0 g of 3- [2- {4-ethoxycarbonylphenylthio) ethyl] -2- (3-pyridyl) indole in 250 ml of 2N hydrochloric acid is heated at the reflux temperature for 6 hours. After cooling, the pH is adjusted to 6 to 7 with saturated aqueous sodium bicarbonate solution (about 500 ml). The resulting product is collected, washed first with water, then with ether and dissolved in 100 ml of hot absolute ethanol. The solution is filtered and treated while still hot with 1.68 ml of 6.5N ethanolic hydrogen chloride. The solution is cooled and diluted with about 100 ml of ether. The resulting 3- [2- (4-carboxyghenylthio) ethyl] -2- (3-gyridyl) indole hydrochloride is collected.

Example 19: A solution of lithium diisopropylamide (LDA) is prepared by adding n-butyllithium (7.66 mM, 1.6 m in hexane) to a solution of diisopropylamine (7.6 mM) in tetrahydrofuran (12 ml) at - 20 ° there. The LDA solution is cooled to -78 ° and with 3- (5-ethoxycarbonylpentyl) -1-methyl-2- (3-pyridyl) -indoi (2.48 g) in tetrahydrofuran (24 ml) dropwise over the course of 5 min offset. The mixture is stirred at -78 ° for 20 min, then phenylselenyl chloride (1.5 g) in tetrahydrofuran (12 ml) is added. After 5 minutes the cooling bath is removed and the mixture is allowed to warm to 0 °. Aqueous sodium bicarbonate solution (60 ml) is added and extra then with ether (3 x 50 ml). The combined organic extracts are washed with saturated sodium bicarbonate solution and sodium chloride solution and dried over anhydrous magnesium sulfate. After concentration in vacuo, crude 3- (5-ethoxycarbonyl-5-phenylselenylpentyl) -1-methyl-2- (3-pyridyl) indole is obtained. The crude selenide is dissolved in dichloromethane (40 ml) and with 30 percent. Hydrogen peroxide (1.8 g, 16 mM) in water (1.8 ml) was added dropwise. After the addition of about 10% of the hydrogen peroxide, the reaction becomes exothermic. The temperature rises to 30 ° at the end of the addition. It is stirred for a further 30 min, then 5 percent. aqueous sodium carbonate solution (40 ml) added. The dichloromethane phase is separated off. The aqueous phase is extracted with dichloromethane (25 ml). The combined organic phases are with 5 percent. washed aqueous sodium carbonate solution, water and sodium chloride and dried over anhydrous magnesium sulfate. After concentration in vacuo, 3- (5-ethoxycarbonylpent-4-enyl) -1-methyl-2- (3-pyridyl) indole is obtained.

Example 20: A solution of the α, β-unsaturated ester 3- (5-ethoxycarbonylpent-4-enyl) -1-methyl-2- (3-pyridyl) indole (84 mg) in methanol (1 ml) is added 1N aqueous lithium hydroxide solution (1 ml) added. The mixture is stirred at room temperature overnight, then evaporated to dryness in vacuo. The residue is dissolved in water (2 ml) and washed with diethyl ether (5 ml). The aqueous phase is brought to pH 6.6 to 7.0 with acid and extracted with dichloromethane. The organic extract is washed with sodium chloride solution, dried over magnesium sulfate and then concentrated in vacuo to 3- (5-carboxypent-4-enyl) -1-methyl-2- (3-pyridyl) indole.

Example 21: To a solution of the Collins reagent, prepared from chromium trioxide (5.6 g) and pyridine (8.86 g, 112 mM) in dichloromethane (150 ml) at 0 to 5 ° under a nitrogen atmosphere, 1 at once , 8 g of 3- (6-hydroxyhexyl) -1-methyl-2- (3-pyridyl) indole in dichloromethane (15 ml) was added. The mixture is stirred for a further 30 min, then filtered through cellite. The filtrate is passed through a Headed silica gel column. The product is eluted from the silica gel with a mixture of ethyl acetate / dichloromethane (500 ml). After concentration in vacuo, 3- (5-formylpentyl) -1-methyl-2- (3-pyridyl) indole is obtained.

Example 22: Trimethyl phosphonoacetate (328 mg) is added dropwise to a solution of potassium tert-butoxide (220 mg) in tetrahydrofuran (5 ml) at 0 ° under a nitrogen atmosphere. The solution is stirred at 0 ° for 20 min, then cooled to -78 °. A solution of 3- (5-formylpentyl) -1-methyl-2- (3-pyridyl) indole (450 mg) in tetrahydrofuran (5 ml) is added dropwise over 15 minutes. The mixture is left at -78 ° for 15 min, then the cooling bath is removed. The mixture is stirred at room temperature overnight, then diluted with water (25 ml) and extracted with diethyl ether (3 x 25 ml). The combined extracts are washed with saturated sodium hydrogen carbonate solution, then with sodium chloride solution and dried over anhydrous magnesium sulfate. After concentration in vacuo, the α, β-unsaturated ester 3- (7-methoxycarbonylhept-6-enyl) -1-methyl-2- (3-pyridyl) indole is obtained.

Example 23: By hydrolysis of 50 mg of 3- (7-methoxycarbonylhept-6-enyl) -1-methyl-2- (3-pyridyl) indole with 1N aqueous lithium hydroxide solution, 3- (7-carboxyhept-6-enyl is obtained ) -1-methyl-2- (3-pyridyl) indole.

Example 24: 3- (7-Carboxyhept-6-enyl) -1-methyl-2- (3-pyridyl) indole (100 mg) is dissolved in 10 ml of absolute ethanol and dissolved in a catalytic amount of 10X palladium -Carbon hydrogenated at a pressure of 1 bar. After the absorption of 1 mol of hydrogen, the catalyst is removed by filtration and washed with a few ml of ethanol. The combined filtrates are concentrated in vacuo; 3- (7-Carboxyheptyl) -1-methyl-2- (3-pyridyl) indole is obtained.

Example 25: 3- (4-cyanobutyl) -2- (3-pyridyl) indole (540 mg) is heated at 185 ° for 0.5 h with 450 mg of powdered sodium hydroxide and 5 ml of ethylene glycol; the reaction solution is diluted with 50 ml of water, washed with ether and adjusted to pH 6 with 2N hydrochloric acid; 3- (4-Carboxybutyl) -2- (3-pyridyl) indole is obtained.

• Zu 6,0 ml einer 2 m Aethylmagnesiumbromidlösung in Tetrahydrofuran wird unter Stickstoffschutz bei 0° tropfenweise im Verlauf von 20 min eine Lösung von 2-(3-Pyridyl)-indol (1,9 g) in 12 ml Tetrahydrofuran gegeben. Das Gemisch wird bei 0° 0,5 h gerührt und dann mit einer Lösung von 1,78 g 5-Bromvaleronitril in 4 ml Tetrahydrofuran behandelt. Dieses Gemisch wird bei 0° 1 h, dann bei Raumtemperatur 1 h gerührt und in 125 ml Eiswasser gegossen. Dieses Gemisch wird zweimal mit je 50 ml Aether extrahiert; der Extrakt wird mit Wasser gewaschen, getrocknet, zur Trockene eingedampft und gereinigt; man erhält 3-(4-Cyanbutyl)-2-(3-pyridyl)-indol.

The starting material is produced as follows:

• A solution of 2- (3-pyridyl) indole (1.9 g) in 12 ml of tetrahydrofuran is added dropwise over a period of 20 min to 6.0 ml of a 2 M ethylmagnesium bromide solution in tetrahydrofuran under nitrogen protection at 0 °. The mixture is stirred at 0 ° for 0.5 h and then treated with a solution of 1.78 g of 5-bromovaleronitrile in 4 ml of tetrahydrofuran. This mixture is stirred at 0 ° for 1 h, then at room temperature for 1 h and poured into 125 ml of ice water. This mixture is extracted twice with 50 ml ether; the extract is washed with water, dried, evaporated to dryness and purified; 3- (4-Cyanbutyl) -2- (3-pyridyl) indole is obtained.

Example 26: A mixture of 540 mg of 3- (4-cyanobutyl) -2- (3-pyridyl) indole, 173 mg of sodium azide, 142 mg of ammonium chloride and 5 mg of lithium chloride in 2 ml of dimethylformamide is heated at 120 ° overnight. After cooling, the mixture is filtered and the filtrate diluted with about 25 ml of water. After adjusting the pH to 10 to 11 with 3N sodium hydroxide solution, the solution is washed with ether in order to remove unreacted nitrile. The aqueous phase is adjusted to pH 5 to 6 with 2N hydrochloric acid and extracted with ether. The ether extract is washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue is cleaned; 3- [4- (5-Tetrazolyi) butyl] -2- (3-pyridyl) indole is obtained.

Example 27:

a) A solution of 2- (3-pyridyl) indole (1.9 g) in 12 ml of tetrahydrofuran is added dropwise over a period of 20 min to 6.0 ml of a 2 M ethylmagnesium bromide solution in tetrahydrofuran under nitrogen protection at 0 °. After the addition is complete, the mixture becomes 0 ° stirred for 0.5 h and then treated dropwise with a solution of 2.39 g of 3- (p-chloromethylphenyl) -2-methyl acrylate in 5 ml of tetrahydrofuran. The resulting mixture is stirred at 0 ° for 1 h, then at room temperature for 1 h and poured into 100 ml of ice water. The resulting mixture is extracted with ether (2 x 50 ml); the organic phase is washed with 100 ml of sodium chloride solution, dried over gastric sodium sulfate and evaporated; 3- [p- (2-Aethoxycarbonylpropen-1-yl) benzyl] -2- (3-gyridyl) indole is obtained.

b) Hydrolysis with 2N aqueous hydrochloric acid gives 3- [p- (2-carboxygropen-1-yl) benzyl] -2- (3-pyridyl) indole.

• Zu einer Suspension von 10,0 g 50% Natriumhydrid (Dispersion in Mineralöl) in frisch destilliertem Dimethoxyäthan (350 ml), die unter Stickstoffschutz bei 10° gerührt wird, werden 53,6 ml 2-Phosphonpropionsäure-triäthylester im Verlauf von etwa 40 min gegeben. Das Gemisch wird gerührt, und zwar 0,5 h bei 10° und dann weitere 1,5 h, in denen man die Temperatur auf Raumtemperatur ansteigen lässt. Diese Lösung wird unter Stickstoffschutz mit einer Kanüle in einen 500 ml-Tropftrichter übergeführt und tropfenweise zu einer Lösung von Terephthalaldehyd (33,53 g) in trockenem Dimethoxyäthan (475 ml) zugegeben, und zwar im Verlauf von 1 h bei 22 bis 34°. Nach beendeter Zugabe wird das Reaktionsgemisch mechanisch bei Raumtemperatur 2 h gerührt, in 1 1 Wasser gegossen und viermal mit je 500 ml Aether extrahiert. Der Aetherextrakt wird mit gesättigter Natriumchloridlösung (700 ml) gewaschen, über Magnesiumsulfat getrocknet, filtriert und im Vakuum zu einem gelben Oel eingeengt, das beim Stehenlassen teilweise kristallisiert. Dieses Rohgemisch wird durch Suspendieren in Petroläther und Aethylacetat (93:7) gereinigt. Das Filtrat wird nach Entfernen des nicht umgesetzten Dialdehyds im Vakuum eingeengt; man erhält ein Gemisch, das durch Hochdruck-Flüssigchromatographie [mit Petroläther/Aethylacetat (93:7)] weiter gereinigt wird. Man erhält den reinen 4-Formyl-a-methylzimtsäure-äthylester. Eine Lösung dieses Aldehyds (34,80 g) in 820 ml absolutem Aethanol wird mit 12,11 g granuliertem Natriumborhydrid bei Raumtemperatur und Stickstoffschutz behandelt. Das entstandene Gemisch wird bei Raumtemperatur 3 h gerührt (oder bis das gesamte Borhydrid aufgelöst ist), dann auf ein Volumen von etwa 200 ml eingeengt, mit 400 ml Wasser verdünnt und dreimal mit je 200 ml Aether extrahiert. Der Aetherextrakt wird mit 100 ml Wasser und Natriumchloridlösung (100 ml) gewaschen, über Magnesiumsulfat getrocknet und filtriert; das Filtrat wird im Vakuum zu 3-(p-Hydroxymethylphenyl)-2-methacrylsäure-äthylester eingeengt. Zu einer Lösung dieses Produkts in 350 ml Methylenchlorid werden bei Raumtemperatur 11,53 ml Thionylchlorid zugegeben, und zwar tropfenweise im Verlauf von 25 min. Die klare farblose Lösung wird 2 h gerührt. Die Lösung wird mit 100 ml Wasser, 200 ml gesättigter Natriumhydrogencarbonatlösung, 100 ml Wasser und 100 ml Natriumchloridlösung gewaschen. Die organische Phase gibt nach dem Trocknen und Entfernen des Lösungsmittels 3-(p-Chlormethylphenyl)-2-methacrylsäure-äthylester, der ohne weitere Reinigung verwendet werden kann.

The starting compound is made as follows:

• 53.6 ml of triethyl 2-phosphonopropionate are added to a suspension of 10.0 g of 50% sodium hydride (dispersion in mineral oil) in freshly distilled dimethoxyethane (350 ml), which is stirred under nitrogen protection at 10 °, over the course of about 40 min given. The mixture is stirred at 0.5 ° for 0.5 h and then for a further 1.5 h, during which the temperature is allowed to rise to room temperature. This solution is cannulated into a 500 ml dropping funnel under nitrogen protection and added dropwise to a solution of terephthalaldehyde (33.53 g) in dry dimethoxyethane (475 ml) over a period of 1 hour at 22 to 34 °. After the addition has ended, the reaction mixture is stirred mechanically at room temperature for 2 h, poured into 1 l of water and extracted four times with 500 ml of ether each time. The ether extract is washed with saturated sodium chloride solution (700 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to a yellow oil which partially crystallizes on standing. This crude mixture is purified by suspending it in petroleum ether and ethyl acetate (93: 7). The filtrate is concentrated in vacuo after removal of the unreacted dialdehyde; a mixture is obtained which is further purified by high pressure liquid chromatography [with petroleum ether / ethyl acetate (93: 7)]. The pure 4-formyl-a-methylcinnamic acid ethyl ester is obtained. A solution of this aldehyde (34.80 g) in 820 ml of absolute ethanol is treated with 12.11 g of granulated sodium borohydride at room temperature and nitrogen protection. The resulting mixture is stirred at room temperature for 3 hours (or until all of the borohydride has dissolved), then concentrated to a volume of about 200 ml, diluted with 400 ml of water and extracted three times with 200 ml of ether each time. The ether extract is washed with 100 ml of water and sodium chloride solution (100 ml), dried over magnesium sulfate and filtered; the filtrate is concentrated in vacuo to ethyl 3- (p-hydroxymethylphenyl) -2-methacrylic acid. 11.53 ml of thionyl chloride are added to a solution of this product in 350 ml of methylene chloride at room temperature, dropwise over the course of 25 min. The clear colorless solution is stirred for 2 hours. The solution is washed with 100 ml of water, 200 ml of saturated sodium bicarbonate solution, 100 ml of water and 100 ml of sodium chloride solution. After drying and removal of the solvent, the organic phase gives ethyl 3- (p-chloromethylphenyl) -2-methacrylic acid, which can be used without further purification.

Example 28: 3- (5-formylpentyl) -1-methyl-2- (3-pyridyl) indole (127 mg) is dissolved in dimethylformamide (0.66 ml) and mixed with pyridinium dichromate (298 mg) all at once. The mixture is stirred at room temperature overnight, then diluted with ether and filtered. The solid is washed with methylene chloride and the combined filtrates are concentrated in vacuo; a product is obtained which is extracted with 0.1N sodium hydroxide solution (2 ml). The aqueous extract is acidified to pH 5.5 to 6.0 and extracted with chloroform. The chloroform extract is dried and concentrated in vacuo, giving the 3- (5-carboxypentyl) -1-methyl-2- (3-pyridyl) indole of Example 3 after purification by chromatography.

Example 29: A solution of 3- (5-carboxypentyl) -5-chloro-1-methyl-2- (3-pyridyl) indole hydrochloride (400 mg) in 7 ml of tetrahydrofuran is heated and 200 mg (0, 27 ml) triethylamine treated. This solution is added dropwise to a solution of 108 mg (0.096 ml) ethyl chloroformate in 1 ml of tetrahydrofuran, which is cooled to 0 to 5 ^* . The reaction mixture is stirred at this temperature for 1 h and filtered to remove triethylamine hydrochloride. The filtrate is treated with a solution of hydroxylamine hydrochloride (69 mg) and sodium hydroxide (40 mg) in 10 ml of methanol. The mixture is stirred for 0.5 h and concentrated in vacuo. The residue is treated with 25 ml ether / methanol (10: 1) and filtered. The filtrate is evaporated in vacuo; the residue is dissolved in acetone and treated with 6.5 N ethanolic hydrogen chloride; 3- (5-Hydroxycarbamoylpentyl) -5-chloro-l-methyl-2- (3-pyridyl) indole hydrochloride is obtained.

Example 30: 3- [7,7- (bis-methoxycarbonyl) heptyl] -1-methyl-2- (3-pyridyl) indole (273 mg) is dissolved in methanol (0.5 ml) and treated with 1N aqueous lithium hydroxide solution (1.95 ml) was added. The mixture is stirred at room temperature for 1 h, then heated under reflux for 2.5 h. The solution is evaporated to dryness; the residue is dissolved in water and the pH is adjusted to 6 to 6.2. The mixture is extracted with methylene chloride. Concentration of the extract after drying over anhydrous magnesium sulfate gives crude 3- [7,7- (bis-carboxy) heptyl] -1-methyl-2- (3-pyridyl) indole.

A sample of the crude dicarboxylic acid (30 mg) is heated with p-xylene (3 ml) containing 0.1N hydrochloric acid (0.1 ml) for 0.5 h. The reaction mixture is allowed to cool to room temperature and extracted with sodium hydroxide solution. The aqueous phase is separated off and extracted with ethyl acetate after adjusting the pH to 6 to 6.2. The organic phase is dried over anhydrous magnesium sulfate and concentrated; 3- (7-Carboxyheptyl) -1-methyl-2- (3-pyridyl) indole is obtained.

• Thionylchlorid (0,36 ml) wird mit 3-(6-Hyeroxyhexyl)-1-methyl-2-(3-pyridyl)-indol (1,37 g) bei 0° vereinigt Das Gemisch wird dann bei Raumtemperatur 1 h gerührt. Gesättigte wi;serige Natriumhydrogencarbonatlösung wird zugegeben, und das G:misch wird mit Dichlormethan extrahiert. Der Extrakt wird mit Utriumchloridlösung gewaschen, über wasserfreiem Magnesiumsulfat getrocknet und im Vakuum eingeengt; man erhält das rohe Chlorid 3-(6-Chlorhexyl)-1-methyl-2-(3-pyridyl)-indol.

The starting connection is made as follows:

• Thionyl chloride (0.36 ml) is combined with 3- (6-hyeroxyhexyl) -1-methyl-2- (3-pyridyl) indole (1.37 g) at 0 °. The mixture is then stirred at room temperature for 1 h. Saturated aqueous sodium bicarbonate solution is added and the mixture is extracted with dichloromethane. The extract is made with Utrium chloride solution washed, dried over anhydrous magnesium sulfate and concentrated in vacuo; the crude chloride 3- (6-chlorohexyl) -1-methyl-2- (3-pyridyl) indole is obtained.

3- (6-chlorohexyl) -1-methyl-2- (3-pyridyl) indole (0.5 g) is mixed with dimethyl malonate (792 mg), potassium carbonate (790 mg) and dimethylformamide (11.6 ml) offset; the mixture is heated at 80 to 90 ° for 18 h under nitrogen. The mixture is poured into ice water (80 ml), acidified with 1N hydrochloric acid and washed with ether. The aqueous phase is adjusted to pH 6 and extracted with ether, which is then dried over anhydrous magnesium sulfate and concentrated; 3- [7,7- (bis-methoxycarbonyl) heptyl] -1-methyl-2- (3-pyridyl) indole is obtained.

Example 31: 3- (6-chlorohexyl) -1-methyl-2- (3-pyridyl) indole (165 mg) in dry tetrahydrofuran (2 ml) is added dropwise to magnesium shavings (12 mg) in dry tetrahydrofuran (2 ml) given in a nitrogen atmosphere. An iodine crystal is added during the addition to start the reaction. After the addition has ended, the mixture is heated under reflux for 4 h, then cooled to 0 °; Dry carbon dioxide is introduced into the flask with stirring for 15 minutes. The mixture is poured into 5 ml of 1N sodium hydroxide solution and extracted with ether. The aqueous phase is adjusted to pH 6 to 6.2 and extracted with ethyl acetate. The organic phase is dried over anhydrous magnesium sulfate and concentrated in vacuo; 3- (6-carboxyhexyl) -1-methyl-2- (3-pyridyl) indole is obtained.

Example 32: A solution of 10.0 g of 2- (3-pyridyl) indole in 60 ml of tetrahydrofuran is added dropwise under nitrogen at 0 to 5 ° over 30 minutes to 30 ml of a 2 M ethylmagnesium bromide solution in tetrahydrofuran. The mixture is stirred at 0 to 5 ° for 0.5 h, then 10.6 g of methyl bromotetrolic acid (J. Chem. Soc. 1950, 3646) in 50 ml of tetrahydrofuran are added dropwise. The mixture is stirred for a further 2 h, poured into ice water at 0 ° and extracted with ether. The aqueous phase is extra with ether here. The ether extract is washed with water and sodium chloride solution and dried over anhydrous magnesium sulfate. Concentration in vacuo gives 3- (3-methoxycarbonyl-prop-2-ynyl) -2- (3-pyridyl) indole.

Example 33: By treating 330 mg of 3- (3-methoxycarbonylprop-2-ynyl) -2- (3-pyridyl) indole in 10 ml of methanol with 3.0 ml of 1N aqueous lithium hydroxide solution at room temperature, 3- (3 -Carboxyprop-2-ynyl) -2- (3-pyridyl) indole.

Example 34:

a) To a solution of 4- (3-indolyl) butyric acid ethyl ester (3.00 g) and imidazole (4.43 g) in dioxane (75 ml), which is stirred at 10 ⁰ , is added dropwise with stirring Solution of bromine (0.65 ml) in dioxane (25 ml) added over 2.5 h. As soon as the bromine is added, the reaction mixture becomes a thick suspension. Additional dioxane (30 ml) is added to keep the reaction mixture stirrable. When the addition is complete, the cooling bath is removed and the reaction mixture is stirred at room temperature overnight. The suspended solid is removed by vacuum filtration and the filtrate is concentrated in vacuo to an orange oil. This oil is suspended in ether (100 ml) and extracted with 1N hydrochloric acid (1 x 50 ml). The aqueous phase is washed with ether (1 x 100 ml), made alkaline with 3N sodium hydroxide solution (12 ml) and extracted with ether (2 x 100 ml). This ether extract is washed with sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo to an orange oil which partially crystallizes. This material (1.38 g) is dissolved in 20 ml of ether; the solution is mixed with 0.65 ml of 7.1 M ethanolic hydrogen chloride. The salt separates as an oil, which crystallizes when a few ml of ethanol is added; 2- (1-imidazolyl) -3- (3-ethoxycarbonylpropyl) indole hydrochloride, mp. 152 to 155 °, is obtained.

b) 2- (1-imidazolyl) -3- (5-ethoxycarbonylpentyl) indole is prepared accordingly; NMR (CDC1 ₃ ): 4.07 (q, 2H), 1.23 (t, 3H), 7.0 to 7.8 (m, 7H).

Example 35:

a) A suspension of 0.20 g of 2- (1-imidazolyl) -3- (3-ethoxycarbonylpropyl) indole hydrochloride in 5 ml of 3N sodium hydroxide solution is stirred at room temperature for 2 hours. Absolute ethanol (5 ml) is then added; the resulting solution is stirred for a further 2.5 h at room temperature. The solution is concentrated in vacuo to remove the ethanol. The resulting solution is acidified to pH 3.5 with 1N hydrochloric acid. The precipitate is collected and dried (50 ° / 33 mbar); 2- (1-imidazolyl) -3- (3-carboxypropyl) indole, mp. 205 to 207 °, is obtained.

b) 2- (1-imidazolyl) -3- (5-carboxypentyl) indole, mp. 146 to 148 °, is prepared accordingly.

Example 36: Potassium tert-butoxide (2.11 g) is added to a suspension of (4-carboxybutyl) triphenylphosphonium bromide (4.17 g) in toluene (50 ml) with stirring and nitrogen protection at room temperature. The suspension is heated to 90 ° and kept at this temperature for 40 min. The resulting suspension is cooled to room temperature and with a solution of l-methyl-2- (3-pyridyl) indole-3-carboxaldehyde (2.00 g) in a mixture of toluene (20 ml) and dimethyl sulfoxide (4 ml) added dropwise. After the addition is complete, the suspension is stirred overnight at room temperature.

The reaction mixture is heated at 60 ° for 3 h, cooled to room temperature and diluted with water (100 ml). The organic phase is separated off and discarded. The aqueous phase is first extracted with toluene (1 x 100 ml) and ether (1 x 100 ml), acidified to pH 1 with 1N hydrochloric acid and extracted with ether (2 x 100 ml). The latter ether extract is dried (magnesium sulfate), filtered and concentrated in vacuo to an oil. Lightning cleaning Chromatography on silica gel with methylene chloride / methanol (97: 3) gives essentially pure 3- (5-carboxypent-l-enyl) -1-methyl-2- (3-pyridyl) indole, which is converted into the hydrochloride (salt) becomes. This is recrystallized from methanol / ether; 3- (S-Carboxypent-I-enyl) -1-methyl-2- (3-pyridyl) indole hydrochloride, mp. 163 to 165 °, is obtained.

• Eine Lösung von 19,7 ml Phenylhydrazin (21,63 g) und 22 ml 3-Acetylpyridin (24,23 g) in Eisessig (100 ml) wird gerührt und 4,5 h unter Rückfluss erhitzt. Die Lösung wird in einem Eiswasserbad gekühlt und mit gesättigter Natriumhydrogencarbonatlösung (180 ml) neutralisiert. Der Niederschlag wird gesammelt, gewaschen und getrocknet; man erhält 3-Acetylpyridinphenylhydrazon.

The starting compound is made as follows:

• A solution of 19.7 ml of phenylhydrazine (21.63 g) and 22 ml of 3-acetylpyridine (24.23 g) in glacial acetic acid (100 ml) is stirred and heated under reflux for 4.5 h. The solution is cooled in an ice water bath and neutralized with saturated sodium hydrogen carbonate solution (180 ml). The precipitate is collected, washed and dried; 3-acetylpyridinephenylhydrazone is obtained.

A mixture of this hydrazone (8.0 g) and polyphosphoric acid (74.0 g) is stirred and heated on a water bath for 1 hour. The mixture is then heated at 135 to 140 ° for 10 minutes. The reaction mixture is poured into 840 ml of water; the precipitate is collected and washed with water. The product is resuspended in 100 ml of ice water and the pH with 50 percent. aqueous sodium hydroxide solution set to 8. The precipitate is collected, washed with cold water and dried; 2- (3-pyridyl) indole, mp. 176 to 177 ° [Bull. Soc. Chim. France 1969, 4154].

Phosphorus oxychloride (3.36 ml) is added dropwise to dimethylformamide (10.6 g), which is kept at 0 to 3 °, over 20 minutes. After the addition is complete, a solution of 2- (3-pyridyl) indole (6.50 g) in dimethylformamide (20 ml) is added dropwise over the course of 30 min so that the reaction temperature does not exceed 10 °. The cooling bath is removed, the viscous solution is heated to 35 to 40 ° and kept at this temperature for 1 h. Crushed ice (50 g) is added to the reaction mixture. A solution of sodium hydroxide (24.4 g) in 65 ml of water is slowly added. After the addition, the resulting red-orange solution is quickly heated under reflux and at the reflux temperature held for about 2 min. The solution is allowed to cool to room temperature and placed in a refrigerator for two days. The resulting precipitate is collected and washed well with water; an orange solid is obtained which is recrystallized from methanol (240 ml); 2- (3-pyridyl) indole-3-carboxaldehyde, mp. 236 to 238 °, is obtained.

Potassium carbonate (3.97 g) is added to a solution of 2- (3-pyridyl) indole-3-carboxaldehyde (2.22 g) in dimethylformamide (20 ml) under nitrogen protection at room temperature. The suspension is stirred at room temperature for 5 minutes. Iodomethane (1.56 g) is added all at once and the resulting suspension is stirred at room temperature overnight. The suspension is then diluted with water (100 ml); the solid is collected, washed with water and dried; l-Methyl-2- (3-pyridyl) indole-3-carboxaldehyde, mp 148 to 150 °, is obtained.

Example 37: A solution of 3- (5-carboxypent-1-enyl) -1-methyl-2- (3-pyridyl) indole (0.51 g) in absolute ethanol (20 ml) containing 10 x palladium on carbon (0.05 g) are added, the mixture is hydrogenated at a pressure of 3 bar for 2 h. The catalyst is filtered off; the filtrate is evaporated to dryness. By treating the residue with absolute ethanol, a white solid is obtained, mp 117 to 120 °. Recrystallization from acetonitrile gives 3- (5-carboxypentyl) -1-methyl-2- (3-pyridyl) indole (the compound of Example 3), mp. 128 to 130 °.

Example 38: According to the methods of the preceding examples, further compounds of the formulas II and III are prepared in which R ₁ '= ^C H ₃ and R ₄ ⁼ OH means:.

Example 39: According to the methods of the preceding examples, further compounds of the formula I are prepared in which R ₁ = CH ₃ , Ar = 3-pyridyl or 1-imidazolyl and B = COOH:

Example 40: 10,000 tablets are produced, each containing 10 mg of the active ingredient:

Composition:

Method:

All powdery components are sieved through a sieve with a mesh size of 0.6 mm. Then the active ingredient, milk sugar, talc, magnesium stearate and half the starch are mixed in a suitable mixer. The other half of the starch is suspended in 40 ml of water and the suspension is added to the boiling solution of the polyethylene glycol in 150 ml of water. The paste formed is added to the powders and optionally granulated with the addition of more water. The granules are dried overnight at 35 °, passed through a sieve with a mesh size of 1.2 mm and pressed to tablets of 6.4 mm in diameter which have a breaking groove.

Example 41: 10,000 capsules are produced, each containing 25 mg of active ingredient:

Composition:

Method:

All powdery components are sieved through a sieve with a mesh size of 0.6 mm. Then the active ingredient is mixed in a suitable mixer first with talc and then with milk sugar until homogeneous. Capsules No. 3 are filled with 200 mg of the mixture obtained using a capsule filling machine.

Correspondingly tablets and capsules are produced which contain about 10 to 100 mg of other compounds according to the invention, e.g. of any other compound described in the examples.

Example 42:

a) To a suspension of sodium hydride (50%, 0.106 g) in dimethylformamide (3 ml), which is kept under nitrogen at room temperature, a solution of ethyl p-mercaptobenzoate (0.40 g) in dimethylformamide (1 ml ) given. The mixture is stirred for half an hour and then a solution of 3- (N, N-dimethylaminomethyl) -2- (3-pyridyl) indole (0.5 g) in dimethylformamide (6 ml) is added dropwise, which at -10 ^{0 is kept} under nitrogen and stirred. The reaction mixture is stirred at room temperature for 18 h. The mixture is poured into ice water and extracted with ether. The ether extract is washed repeatedly with water, dried over magnesium sulfate, filtered and concentrated to give 3 - [(p-ethoxycarbonylphenylthio) methyl] -2- (3-pyridyl) indole.

• Zu einer Mischung aus 40% Dimethylamin-Lösung (4,5 ml), 37 % wässeriger Formaldehyd-Lösung (2,6 ml) und Eisessig (6,4 ml), die bei 10° gerührt wird, wird portionsweise 2-(3-Pyridyl)-indol (5,0 g) hinzugegeben. Nach beendeter Zugabe wird das Reaktionsgemisch 3 h bei Raumtemperatur gerührt. Das Gemisch wird mit konzentrierter wässeriger Ammoniaklösung basisch gemacht, dann das Produkt gesammelt, wobei man 3-(N,N-Dimethylaminomethyl)-2-(3-pyridyl)-indol erhält.

The starting compound is made as follows:

• To a mixture of 40% dimethylamine solution (4.5 ml), 37% aqueous formaldehyde solution (2.6 ml) and glacial acetic acid (6.4 ml), which is stirred at 10 °, 2- (3rd -Pyridyl) indole (5.0 g) added. When the addition is complete, the reaction mixture is stirred at room temperature for 3 h. The mixture is made basic with concentrated aqueous ammonia solution, then the product is collected to give 3- (N, N-dimethylaminomethyl) -2- (3-pyridyl) indole.

b) Hydrolysis of 3 - [(p-ethoxycarbonylphenylthio) methyl] -2- (3-pyridyl) indole with 2N hydrochloric acid gives 3 - [(p-carboxyphenylthio) methyl] -2- (3rd pyridyl) indole.

Example 43: A mixture of 0.01 mol of 7- [o- (N-nicotinoyl-N-methylamino) phenyl] heptanoic acid and 2 molar equivalents of potassium tert-butoxide in 50 ml of tetrahydronaphthalene is added overnight under nitrogen Reflux cooked. The reaction is stopped by adding water and the mixture is evaporated to dryness under reduced pressure. Water and methylene chloride are added and the pH is adjusted to 5 with 2N hydrochloric acid.

The methylene chloride phase is separated off, washed with water and evaporated to dryness. After recrystallization of the residue from acetonitrile, 3- (5-carboxypentyl) -1-methyl-2- (3-pyridyl) indole from Example 3, mp. 128-130 ^{* is obtained} .

• Zunächst wird l-Aza-2,3-benzocyclodek-2-en-10-on durch eine Beckmann-Umlagerung aus 1,2-Benzocyclonon-1-en-3-on-0xim hergestellt [Chem. Ber. 90, 1946 (1957)].

The starting compound is made as follows:

• First, l-aza-2,3-benzocyclodek-2-en-10-one is produced by a Beckmann rearrangement from 1,2-benzocyclonon-1-en-3-one-0xim [Chem. Ber. 90, 1946 (1957)].

A solution of 1-aza-2,3-benzocyclodek-2-ene is added dropwise to a suspension of 50 × sodium hydride (0.50 g) in anhydrous dimethylformamide (20 ml), which is stirred under nitrogen at room temperature. 10-one (2.03 g) placed in dimethylformamide (10 ml). The mixture is stirred for half an hour at room temperature, then methyl iodide (1.56 g) is added dropwise. When the addition is complete, the reaction mixture is stirred at room temperature for 5 h. The mixture is poured into ice water and extracted repeatedly with ether. The ether extract is washed with water and with saturated saline, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give N-methyl-1-aza-2,3-benzocyclodek-2-en-10-one.

A mixture of N-methyl-l-aza-2,3-benzocyclodek-2-en-10-one (1.09 g) and 3N sodium hydroxide solution (20 ml) is boiled under reflux with stirring for 18 h. The solution is cooled and acidified to pH 4 with 3N hydrochloric acid. The product is extracted with methylene chloride. This extract is washed with water, dried over magnesium sulfate, filtered and concentrated to give 7- [o- (N-methylamino) phenyl] heptanoic acid.

Nicotinoyl chloride hydrochloride is added to a mixture of 7- [o- (N-methylamino) phenyl] heptanoic acid (1.18 g) and triethylamine (1.21 g) in toluene (50 ml), which is stirred at room temperature (0.89 g) added in portions. After the addition has ended, the mixture is boiled under reflux for 6 h. The suspension is cooled in Ice water and collects the precipitation. This is suspended in chloroform and collected again to give 7- [o- (N-nicotinoyl-N-methylamino) phenyl] heganoic acid.

Claims (19)

1. Process for the preparation of 2- (pyridyl and imidazelyl) indoles of the formula 1

where R _{1 is} hydrogen or lower alkyl, Ar in each case represents 3-pyridyl or I-imidazolyl which is unsubstituted or substituted by lower alkyl, carboxy, lower alkoxycarbonyl or carbamoyl, R ₂ and R ₃ independently of one another are hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy, Lower alkoxy, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy, lower alkoxycarbonyl or lower alkyl- (thio, sulfinyl or sulfonyl), or R ₂ and R ₃ together, on adjacent carbon atoms, are lower alkylenedioxy; A alkylene having 3 to 12 carbon atoms, the number of carbon atoms between the indole nucleus and group B being 3 to 12, alkenylene or alkynylene each having 2 to 12 carbon atoms, lower alkylenephenylene-lower (alkylene or alkenylene), lower alkylene-phenylene, Lower alkylene (thio or oxy) lower alkylene, lower alkylene (thio or oxy) phenylene or lower alkylene phenylene (thio or oxy) lower alkylene means and B represents carboxy, esterified carboxy, carbamoyl, mono- or di-lower alkylcarbamoyl, hydroxymethyl, cyano, hydroxycarbamoyl, 5-tetrazolyl or formyl; their imidazolyl or pyridyl N-oxides, and their salts, characterized in that one 1) a compound of formula IV

wherein R ₁ , R _{2 '} R ₃ , A and B have the meaning given under formula I and X represents halogen, with a compound of formula Ar-H or a reactive metalated derivative thereof, wherein Ar has the meaning given under formula I. , and, if desired, converting a compound of formula I, wherein R _{1 is} hydrogen, with an alkylating agent into a compound of formula I, wherein R _{1 is} lower alkyl, or 2) a compound of formula V

wherein R ₁ , R ₂ , R ₃ and Ar have the meaning given under formula I, as a reactive organometallic derivative with a reactive functional derivative of a compound of formula VI

in which A and B have the meaning given under formula I, and, if desired, converting a compound of formula I obtained, in which R _{1 is} hydrogen, with an alkylating agent into a compound of formula I in which R _{1 is} lower alkyl, or 3) a compound of formula VII

wherein R _I , R ₂ , R ₃ , A and B have the meaning given under formula I and Ar is unsubstituted or substituted as indicated under formula I, 3-pyridyl, ring-closes, or 4) a compound of formula VIII

wherein Ar, R ₁ , R ₂ , R ₃ , A and B have the meaning given under formula I, cyclized, or 5) for the preparation of a compound of the formula I, in which A is, for example, alkenylene, a compound of the formula Va under the conditions of a Wittig reaction

which corresponds to a 3-formyl derivative of a compound of formula V, with the ylide of a compound of formula XII

in which B has the meaning given under formula I, A 'is, for example, alkylene as defined above for A in compounds of the formula I, but with a chain length reduced by 1 carbon atom, and R _{5 is} a dialkylphosphono- or triarylphosphonium radical, is reacted or 6) for the preparation of a compound of the formula I, in which, for example, A is lower alkyl (thio or oxy) lower alkylene or lower alkylene (thio or oxy) phenylene, a compound of the formula Vb

wherein Ar, R ₁ , R ₂ and R _{3 have} the meaning given under formula 1 and R ₆ and R ₇ each represent lower alkyl - that is a 3- (disubstituted aminomethyl) derivative of a compound of formula V with, for example, a compound of formula XIII

or a reactive alkali metal or ammonium derivative thereof, in which B is as defined under formula I, R ₅ 'is hydroxy or thiol and A "is, for example, lower alkylene or phenylene; or with, for example, a lactone or thiolactone of a compound of the formula XIII , wherein R ₅ 'is hydroxy or thiol, A "is lower alkylene and B is carboxy, or 7) a compound of formula Ia

wherein A, Ar, R ₁ , R ₂ and R _{3 have} the meaning given under formula I and C is a group different from B and convertible into B, optionally with the chain A being extended within the scope of its definition, or a compound of the formula I. ^* or Ia ^* , which is the same as that of formula 1 or Ia, but in which A is alkylene with 1 or 2 carbon atoms, with extension of the alkylene chain A to alkylene with a number of carbon atoms as defined under formula I, in one Converts compound of formula I; wherein interfering reactive groups in the molecule are optionally temporarily protected, and / or, if desired, converting a compound of formula I obtained into another compound of the invention, and / or, if desired, a free compound of formula I obtained into a salt or converting an obtained salt into the free compound or into another salt, and / or, if desired, separating an obtained mixture of isomers or racemates into the individual isomers or racemates, and / or, if desired, splitting obtained racemates into the optical antipodes . 2. The method according to claim 1, characterized in that compounds of the formula I in which R _{1 is} hydrogen or lower alkyl, Ar is in each case unsubstituted or substituted by lower alkyl, 3-pyridyl or 1-imidazolyl, R ₂ and R ₃ independently of one another are hydrogen, Lower alkyl, halogen, trifluoromethyl, hydroxy, lower alkoxy or lower alkylthio, or R ₂ and R ₃ together, on adjacent carbon atoms, are lower alkylenedioxy; A represents alkylene with 4 to 12 carbon atoms, lower (alkylene-phenylene, alkylene-thiophenylene or alkylene-oxy-phenylene) with 7 to 10 carbon atoms; B represents carboxy, lower alkoxycarbonyl, carbamoyl, cyano, hydroxycarbamoyl, 5-tetrazolyl or hydroxymethyl; and make their salts. 3. The method according to claim 1, characterized in that compounds of the formula II

wherein R ₁ 'is hydrogen or lower alkyl, R ₂ ' and R ₃ 'independently of one another are hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy, lower alkylthio or lower alkoxy, or R ₂ ' and R ₃ 'together, on adjacent carbon atoms, are methylenedioxy , m is an integer from 4 to 12 and R _{4 is} hydroxy, lower alkoxy or amino; and their pharmaceutically acceptable salts. 4. The method according to claim 3, characterized in that compounds of the formula II in which R ₁ 'is hydrogen or lower alkyl, R ₂ ' is hydrogen or halogen, R ₃ 'is hydrogen, m is an integer from 4 to 8 stands and R _{4 is} hydroxy, lower alkoxy or amino, and prepares their pharmaceutically acceptable salts. 5. The method according to claim 1, characterized in that compounds of formula III

wherein R ₁ 'is hydrogen or lower alkyl, R ₂ ' and R ₃ 'independently of one another are hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy, lower alkylthio or lower alkoxy, or R ₂ ' and R ₃ 'together, on adjacent carbon atoms, are methylenedioxy , m is an integer from 3 to 12 and R _{4 is} hydroxy, lower alkoxy or amino, and prepares their pharmaceutically acceptable salts. 6. The method according to claim 5, characterized in that compounds of the formula III in which R ₁ 'is hydrogen or lower alkyl, R ₂ ' is hydrogen or halogen, R ₃ 'is hydrogen, m is an integer from 4 to 8 stands and R _{4 is} hydroxy, lower alkoxy or amino, and prepares their pharmaceutically acceptable salts. 7. The method according to claim 1, characterized in that 3- (5-carboxypentyl) -2- (3-pyridyl) indole and pharmaceutically acceptable salts thereof are prepared. 8. The method according to claim 1, characterized in that 3- (5-carboxypentyl) -1-methyl-2- (3-pyridyl) indole and pharmaceutically acceptable salts thereof are prepared. 9. The method according to claim 1, characterized in that 5-hydroxy-2- (3-pyridyl) -3- (5-carboxypentyl) indole and pharmaceutically acceptable salts thereof are prepared. 10. The method according to claim 1, characterized in that one produces 3- (5-carboxypentyl) -5-chloro-2- (3-pyridyl) indole and pharmaceutically usable salts thereof. 11. The method according to claim 1, characterized in that 3- (5-carboxypentyl) -5-chloro-l-methyl-2- (3-pyridyl) indole and pharmaceutically acceptable salts thereof are prepared. 12. The method according to claim 1, characterized in that 2- (1-imidazolyl) -3- (3-carboxypropyl) indole and pharmaceutically acceptable salts thereof are prepared. 13. The method according to claim 1, characterized in that 2- (1-imidazolyl) -3- (5-carboxypentyl) indole and pharmaceutically acceptable salts thereof are prepared. 14. A process for the preparation of compounds of formula I according to claim 1, characterized in that 1) a compound of formula IV

wherein R ₁ , R ₂ , R ₃₁ A and B have the meaning given under formula I and X represents halogen, with a compound of formula Ar-H or a reactive metalated derivative thereof, in which Ar has the meaning given under formula I, and, if desired, converting a resulting compound of formula I, wherein R _{1 is} hydrogen, with an alkylating agent into a compound of formula I, wherein R _{1 is} lower alkyl, or 2) a compound of formula V

wherein R ₁ , R ₂ , R ₃ and Ar have the meaning given under formula I, as a reactive organometallic derivative with a reactive functional derivative of a compound of formula VI

wherein A and B have the meaning given under formula I, wherein interfering reactive groups in the molecule are optionally temporarily protected, and, if desired, a compound of formula I obtained, wherein R is hydrogen, with an alkylating agent into a compound of formula I where R _{1 is} lower alkyl, or 3) a compound of formula VII

wherein R ₁ , R ₂₁ R ₃ , A and B have the meaning given under formula I and Ar is unsubstituted or substituted as indicated under formula I, ring-closes, or 4) a compound of formula VIII

wherein Ar, R ₁ , R ₂ , R ₃ , A and B have the meaning given under formula 1 and Ar denotes unsubstituted or as defined under formula I substituted 3-pyridyl, cyclizes, or 5) a compound of formula Ia

wherein A, Ar, R ₁ , R ₂ and R _{3 have} the meaning given under formula I and C denotes a group which is different from B and can be converted into B, is converted into a compound of the formula I; and converting a compound of formula I obtained by the methods described above into another compound of the invention, and converting a free compound of formula I obtained by the methods described above into a salt or an obtained salt in the free compound, and if desired , an optical or geometric isomer isolated from a mixture of isomers of the compound of formula I obtained. 15. A process for the preparation of pharmaceutical preparations, characterized in that a compound of the formula I obtained by the process according to claim 1 or a pharmaceutically acceptable salt of such a compound is mixed with a pharmaceutically acceptable carrier material. 16. A process for the preparation of pharmaceutical preparations, characterized in that a compound of the formula I obtained by the process according to claim 14 or a pharmaceutically acceptable salt of such a compound is mixed with a pharmaceutically acceptable carrier material.